Asymmetric 1,3-Dipolar Cycloaddition Reactions - Chemical

Chem. Rev. 1998, 98, 863−909

863

Asymmetric 1,3-Dipolar Cycloaddition Reactions Kurt V. Gothelf and Karl Anker Jørgensen* Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark Received October 2, 1997 (Revised Manuscript Received November 20, 1997)

Contents 1. Introduction 2. Basic Aspects 3. Nitrones 3.1. Chiral Nitrones 3.2. Chiral Alkenes 3.3. Intramolecular Reactions 3.4. Metal-Catalyzed Reactions 4. Nitronates 5. Azomethine Ylides 5.1. Chiral Azomethine Ylides 5.2. Chiral Alkenes 5.3. Intramolecular Reactions 5.4. Metal-Catalyzed Reactions 6. Other Allyl Anion Type Dipoles 6.1. Azomethine Imines 6.2. Carbonyl Oxides 7. Nitrile Oxides 7.1. Chiral Nitrile Oxides 7.2. Chiral Alkenes 7.3. Intramolecular Reactions 7.4. Metal-Catalyzed Reactions 8. Diazoalkanes 8.1. Chiral Alkenes 8.2. Asymmetric Catalysis 9. Azides 9.1. Intramolecular Reactions 10. Other Allenyl/Propargyl Anion Type Dipoles 10.1. Nitrile Imines 11. Other Types of 1,3-Dipoles 12. Final Remarks 13. Abbreviations 14. Acknowledgments 15. References

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1. Introduction The addition of a 1,3-dipole to an alkene for the synthesis of five-membered rings is a classic reaction in organic chemistry. The 1,3-dipolar cycloaddition (1,3-DC) reactions are used for the preparation of molecules of fundamental importance for both academia and industry. The history of 1,3-dipoles goes back to Curtius, who in 1883 discovered diazoacetic ester.1 Five years later his younger colleague Buchner studied the reaction of diazoacetic ester with R,β-unsaturated esters and described the first 1,3-DC reaction.2 In

Kurt Vesterager Gothelf (b. 1968) performed the first years of his Ph.D. studies under direction of Professor K. B. G. Torssell at Aarhus University and received his Ph.D. degree in November 1995 working under Professor K. A. Jørgensen at the same university. Following a period as a Postdoctoral Fellow in Professor Jørgensen’s group, he joined Professor M. C. Pirrung’s group at Duke University, where he is currently working on combinatorial chemistry.

Karl Anker Jørgensen (b. 1955) is Professor at Aarhus University. Following a Ph.D. from Aarhus University 1984 and a post-doctoral period with Roald Hoffmann, Cornell University, he joined the Aarhus University faculty. The development and understanding of metal-catalyzed reactions in organic chemistry is the main goal of his research.

1893 he suggested that the product of the reaction of methyl diazoacetate and methyl acrylate was a 1-pyrazoline and that the isolated 2-pyrazole was formed after rearrangement of the 1-pyrazole.3 Five years later nitrones and nitrile oxides were discovered by Beckmann, and Werner and Buss, respectively.4,5 The Diels-Alder reaction was found in 1928,6 and the synthetic value of this reaction soon became obvious. The chemistry of the 1,3-DC reaction has thus evolved for more than 100 years, and a

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864 Chemical Reviews, 1998, Vol. 98, No. 2

variety of different 1,3-dipoles have been discovered.7 However, only a few dipoles have found general application in synthesis during the first 70 years after the discovery of the diazoacetic ester. Two wellknown exceptions are ozone and diazo compounds.8,9 The general application of 1,3-dipoles in organic chemistry was first established by the systematic studies by Huisgen in the 1960s.10 At the same time, the new concept of conservation of orbital symmetry, developed by Woodward and Hoffmann, appeared.11,12 Their work was a milestone for the understanding of the mechanism of concerted cycloaddition reactions. On the basis of the concept by Woodward and Hoffmann, Houk et al. have further contributed to our present understanding and ability to predict relative reactivity and regioselectivity, of 1,3-DC reactions.13-15 The development of 1,3-DC reactions has in recent years entered a new stage as control of the stereochemistry in the addition step is now the major challenge. The selectivity challenge is to control the regio-, diastereo-, and enantioselectivity of the 1,3DC reaction. The stereochemistry of the 1,3-DC reaction can be controlled by either choosing the appropriate substrates or controlling the reaction by a metal complex acting as a catalyst. Compared to the development of the asymmetric metal-catalyzed carbo- and hetero-Diels-Alder reactions, the development of the analogous approach to asymmetric 1,3-DC reactions is several years behind. Probably the most important aspect of the 1,3-DC reaction is to control diastereo- and enantioselectivity and the present review is devoted to this topic. The enantioselectivity can be controlled by either choosing a chiral 1,3-dipolesif possiblesozone and nitrous oxide are exceptions, a chiral alkene, or a chiral catalyst of which the latter probably has the greatest potential. The present review will mainly try to cover the development of the asymmetric 1,3-DC reactions with alkenes, but the application in natural product synthesis will also be described in some cases. This review will deal with the asymmetric 1,3-DC reactions of a series of dipoles with alkenes. For each of the major 1,3-DC reactions the following topics will be presented: reactions of chiral 1,3-dipoles, chiral alkenes, intramolecular 1,3-DC reactions, and metalcatalyzed 1,3-DC reactions. The review will also be restricted to primarily cover reactions in which the 1,3-DC product is optically active. When the reaction described is racemic, this will be indicated.

2. Basic Aspects A 1,3-dipole is defined as an a-b-c structure that undergoes 1,3-DC reactions and is portrayed by a dipolar structure as outlined in Figure 1.7,16,17 Basically, 1,3-dipoles can be divided into two different types: the allyl anion type and the propargyl/allenyl anion type. The allyl anion type is characterized by four electrons in three parallel pz orbitalss perpendicular to the plane of the dipole and that the 1,3-dipole is bent. Two resonance structures in which the three centers have an electron octet, and two structures in which a or c has an electron sextet, can be drawn. The central atom b can be nitrogen,

Gothelf and Jørgensen

Figure 1. The basic resonance structure of 1,3-dipoles.

oxygen, or sulfur (Figure 1A). The propargyl/allenyl anion type has an extra π orbital located in the plane orthogonal to the allenyl anion type molecular orbital (MO), and the former orbital is therefore not directly involved in the resonance structures and reactions of the dipole. The propargyl/allenyl anion type is linear and the central atom b is limited to nitrogen (Figure 1B). The three sextet resonance structures that also can be drawn are omitted in Figure 1. The 1,3-dipoles are occasionally presented as hypervalent structures (Figure 1C). The 1,3-dipoles consist mainly of elements from main group IV, V, and VI. Since the parent 1,3dipoles consist of elements from the second row, and considering the above limitations on the central atom of the dipole, a limited number of structures can be formed by permutations of nitrogen, carbon, and oxygen. Higher row elements such as sulfur and phosphorus can also be incorporated in 1,3-dipoles, but according to our knowledge, only few asymmetric reactions involving these types of dipoles have been published. Hence, 12 dipoles of the allyl anion type and 6 dipoles of the propargyl/allenyl anion type are obtained. The classification and presentation of the parent 1,3-dipoles is depicted in Table 1.7 The 1,3-DC reaction of the parent 1,3-dipoles, with alkenes, and alkynes involves 4 π electrons from the dipole and 2 π electrons from the alkene. If the 1,3DC reaction proceeds via a concerted mechanism it is thermally allowed with the description [π4s + π2s] according to the Woodward-Hoffmann rules.11 This means that the three pz orbitals of the 1,3-dipole and the two pz orbitals of the alkene both combine suprafacially. However, in the 1960s the reaction

Asymmetric 1,3-Dipolar Cycloaddition Reactions Table 1. Classification of the Parent 1,3-Dipoles

Scheme 1

mechanism was subject to a great deal of debate.5 This dispute will be described only briefly. On the basis of an extraordinary series of investigations which led to a monumental collection of data Huisgen et al. developed a detailed rationale for a concerted mechanism for the 1,3-DC reaction (Scheme 1, eq 1). Firestone considered the 1,3-DC reaction to proceed via a singlet diradical intermediate (Scheme 1, eq 2). Both sides in the debate based their arguments on a series of experimental facts.5 On the basis of the stereospecificity of the 1,3-DC reaction, the dispute was settled in favor of the concerted mechanism: The 1,3-DC reaction of benzonitrile oxide with transdideuterated ethylene gave exclusively the transisoxazoline (Scheme 1, eq 3). A diradical intermediate would allow for a 180° rotation of the terminal bond and would thus be expected to yield a mixture of the cis and trans isomers. Huisgen et al. have

Chemical Reviews, 1998, Vol. 98, No. 2 865

later shown that the 1,3-DC reaction can take place by a stepwise reaction involving an intermediate and in these cases the stereospecificity of the reaction may be destroyed. The transition state of the concerted 1,3-DC reaction is thus controlled by the frontier molecular orbitals (FMO) of the substrates. The LUMOdipole can interact with the HOMOalkene and the HOMOdipole with the LUMOalkene. Sustman has classified 1,3-DC reactions into three types, on the basis of the relative FMO energies between the dipole and the alkene (Figure 2).14,15,18,19 In type I 1,3-DC reactions the dominant FMO interaction is that of the HOMOdipole with the LUMOalkene as outlined Figure 2. For type II 1,3-DC reactions the similarity of the dipole and alkene FMO energies implies that both HOMO-LUMO interactions are important. 1,3-DC reactions of type III are dominated by the interaction between the LUMOdipole and the HOMOalkene. 1,3-DC reactions of type I are typical for substrates such as azomethine ylides and azomethine imines, while reactions of nitrones are normally classified as type II. 1,3-DC reactions of nitrile oxides are also classified as type II, but they are better classified as borderline to type III, since nitrile oxides have relatively low lying HOMO energies. Examples of type III interactions are 1,3-DC reactions of ozone and nitrous oxide. However, the introduction of electron-donating or electron-withdrawing substituents on the dipole or the alkene can alter the relative FMO energies, and therefore the reaction type dramatically. The 1,3-DC reaction of N-methyl-Cphenylnitrone with methyl acrylate is controlled by the HOMOdipole-LUMOalkene interaction, whereas the 1,3-DC reaction of the same nitrone with methyl vinyl ether is controlled by the LUMOdipole-HOMOalkene interaction. It should be noted that there is some confusion about the Sustmann classification. Some authors classify the 1,3-dipoles into type I, II, and III, respectively, and this interpretation of the Sustmann classification, no attention is taken to the FMO energies of the alkene. The presence of metals, such as a Lewis acid, in 1,3-DC reactions, can alter both the orbital coefficients of the reacting atoms and the energy of the frontier orbitals of both the 1,3-dipole or the alkene depending on the electronic properties of these reagents or the Lewis acid. The coordination of a Lewis acid to the 1,3-dipole, or the alkene, is of fundamental importance for asymmetric 1,3-DC reactions since the metal can catalyze the reaction. Furthermore, the Lewis acid may also have influence on the selectivity of the 1,3-DC reaction, since both regio-, diastereo-, and enantioselectivity can be controlled by the presence of a metal-ligand complex. The catalytic effect of a Lewis acid on the 1,3-DC reaction can be accounted for by the FMOs of either the 1,3-dipole, or the alkene, when coordinated to the metal. The influence of the coordination of a 1,3dipole or an alkene to a Lewis acid is presented in Figure 3 for type I and III interactions. The reactivity of the 1,3-dipole with an alkene can be accounted for by using a simple frontier orbital



Figure 2. The classification of 1,3-DC reactions on the basis of the FMOs: type I, a HOMOdipole-LUMOalkene interaction; type II, interaction of both HOMOdipole-LUMOalkene and LUMOdipole-HOMOalkene; type III, a LUMOdipole-HOMOalkene interaction.

Figure 3. The change in frontier orbitals by coordination of a Lewis acid to the alkene (left) and to the dipole (right).

line of reasoning, i.e., the energy term from secondorder perturbation theory

∆E ∝

cHOMOcLUMO EHOMO - ELUMO

(4)

where cHOMO and cLUMO are the orbital coefficients at the reacting atoms in the HOMO and LUMO, respectively. The EHOMO - ELUMO in the denominator is the energy difference between the HOMO and LUMO. In eq 4, which is a very simplified expression of the second-order perturbation theory, it is assumed that it is only the HOMO-LUMO interaction which mainly determines the reactivity. The coordination of a Lewis acid to the alkene, e.g., via a conjugated carbonyl group (Figure 3, left) will lower the energy of the FMOs of the alkene, relative to uncoordinated alkene. The lowering in energy of the LUMOalkene will lead to a decrease in the energy difference between EHOMO of the dipole and ELUMO of the alkene coordinated to the Lewis acid, compared to the interaction in the absence of the Lewis acid. The decrease in ELUMO of the alkene coordinated to the Lewis acid leads to an increase in ∆E in eq 4 and thus a faster reaction should be expected. In a similar manner will coordination of a Lewis acid to the dipole lower the energy of the FMOs of the dipole, relative to uncoordinated dipole (Figure 3, right) and a similar argument as above will also lead to an increased reactivity in this case, compared to the 1,3DC reaction in the absence of a catalyst. In this simplified version the increase in reactivity of the 1,3-

dipole and the alkene in the presence of metal catalysts is due to a change of the FMO energy of the substrate interacting with the catalyst. However, it should also be mentioned that other factors as the coordination ability of the substrate to the Lewis acid can alter the reactivity significantly. Concerted cycloaddition reactions are among the most powerful tools for stereospecific creation of new chiral centers in organic molecules. When 1,2disubstituted alkenes are involved in concerted [π4s + π2s] cycloaddition reactions with 1,3-dipoles, two new chiral centers can be formed in a stereospecific manner due to the syn attack of the dipole on the double bond. In the 1,3-DC reactions considered in this review, substrates such as nitrones, may also lead to formation of a new chiral center at the carbon atom of the nitrone. If the alkene, or the 1,3-dipole, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated, leading to a diastereoselective reaction. This type of selectivity will be referred to as diastereofacial selectivity and will be given as diastereomeric excess (de). The term enantioselectivity will only be applied when optically active products are obtained from achiral or racemic starting materials. The endo/exo selectivity is also defined as diastereoselectivity, but for clarity, the term endo/ exo selectivity, or occasionally cis/trans selectivity, will be used and this type of selectivity will be given as a ratiosendo:exo. For the reaction of a 1,3-dipole, such as a nitrone, with an alkene, a pair of diaster-

Asymmetric 1,3-Dipolar Cycloaddition Reactions


Figure 4. Endo selectivity of the Diels-Alder reaction compared the with endo and exo selectivity in the 1,3-DC reaction.

eomers, the endo and exo isomers can be formed (eq 5).

The nomenclature endo and exo is well-known from the Diels-Alder reaction.11 The endo isomer arises from the reaction in which the transition state is stabilized by secondary π orbital interactions as outlined in Figure 4. The same nomenclature is also applied to the 1,3-DC reaction of alkenes with nitrones and other dipoles, but the actual interaction of the N-nitrone pz orbital with a vicinal pz orbital on the alkene, and thus the stabilization, is small.20 The endo/exo selectivity in the 1,3-DC reaction is therefore primarily controlled by the structure of the substrates or by a catalyst.

3. Nitrones The 1,3-DC reactions of nitrones 1 with alkenes 2 leading to isoxazolidines 3 is a fundamental reaction in organic chemistry and the available literature on this topic of organic chemistry is vast (eq 6). In this

major reason for the synthetic utility of this reaction is the variety of attractive compounds which are available from isoxazolidines 3. Important β-amino alcohols 4 can be obtained from isoxazolidine ring upon reduction, with retention of the configuration at the chiral centers (eq 7).

The most common reductive ring-opening reactions are catalytic hydrogenation with palladium or Raney nickel or treatment of the isoxazolidine with zinc and acid, but a variety of other methods are also accessible.21,22 The primary amine is often desired, and to obtain this the N-substituent in the isoxazolidine ring is occasionally removed during the reduction step. β-Amino alcohols obtained in this manner are important building blocks in total synthesis, and there are numerous of examples on the synthesis of optically active natural products. Recently, the reactions between nitrones and alkenes leading to optically active isoxazolidines have been reviewed by Frederickson23 and in this review a number of examples were given on the application of asymmetric nitrone-alkene 1,3-DC reactions in the synthesis of target molecules. Hence, we have tried to accentuate some other parts of this area, especially reactions in which metal complexes have been applied.

3.1. Chiral Nitrones

reaction until three contiguous asymmetric centers can be formed as outlined for the reaction between nitrone 1 and an 1,2-disubstituted alkene 2 in eq 6. The relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkene. 1,3-DC reactions of nitrones with alkenes have found general application in organic synthesis. The

The presentation of intermolecular 1,3-DC reactions involving chiral nitrones is divided into three parts. First, reactions in which the chiral substituent on the nitrone is located at the nitrogen atom will be described, then reactions in which the chiral center is located at the carbon atom, and finally reactions of chiral cyclic nitrones. The most commonly used chiral substituent at the nitrogen atom is the 1-phenylethyl group.24-30 The derived nitrones 7 are available from 1-phenethylamine 5 (Scheme 2) and the substituent has the advantage that it can be removed from the resulting isoxazolidine product 8, by hydrogenolysis. In the

868 Chemical Reviews, 1998, Vol. 98, No. 2 Scheme 2

reduction step the isoxazolidine ring 8 is also opened to give the primary 3-amino alcohol 9 as outlined in Scheme 2. Nitrones 7, bearing the 1-phenylethyl substituent at the nitrogen atom and with different substituents at the carbon atom, have been subjected to 1,3-DC reactions, e.g., with styrene 10.26,28 The reactions proceed to give a mixture of the exo and endo isomers in ratios between 68:32 to 87:13 (eq 8). The diastereofacial selectivity of the reaction is fair to excellent. The product exoa-11 and endoa-11 are formed by addition of styrene to the si face of the nitrone. exob11 and endob-11 to the re face. The minor endo isomers are occasionally obtained with a de close to 100%.

Tice and Ganem have applied nitrone 12 in a 1,3DC reaction with allyl alcohol (eq 9).29 In this reaction, only the two diastereomers 13 and 14 can be formed, since the nitrone carbon atom is not prochiral. Disappointingly, the reaction gave 13 and 14 in a 1:1 ratio. However, the two diastereomers can be separated to give the enantiomerically pure Scheme 3


products. By further reactions of isoxazolidine 13, the natural product (+)-hypusine was obtained.

Kametani et al. applied 1,3-DC reactions of N-Rmethylbenzyl nitrones with benzyl crotonates in the synthesis of (+)- and (-)-thienamycin and penem and carbapenem precursors.27,30 In a similar manner, Overton et al. have applied this type of nitrones in the 1,3-DC reaction with vinyl acetates for the synthesis of naturally occurring β-amino acids.25 The R-methylbenzyl group offers relatively poor discrimination, since mixtures of diastereomers are generally obtained in reactions of this type of nitrones. Another type of nitrones bearing the chiral substituent at the nitrogen atom was developed by Vasella et al.31-36 The optically active nitrones are obtained in an elegant manner from inexpensive glycosides. When partially protected D-mannose oxime 15 reacts with formaldehyde or acetone, nitrones 16a,b, respectively, are formed (Scheme 3).31,36 In the presence of methyl methacrylate, 16a,b react in a 1,3-DC reaction to give the isoxazolidines 17a,b as a mixture of two diastereomers. One of the advantages of this method developed by Vasella et al. is that the chiral auxiliary is easily recovered upon acidic hydrolysis. The N-unsubstituted isoxazolidine 18a,b are formed with optical purities of 79% and 90% ee, respectively. Recently, analogous nitrones have been applied by others in the synthesis of (2S)-4-oxopipecolic acid.37 Vasella et al. have also applied partly protected D-ribofuranose oximes for the formation of optically active nitrones.31,32 However, the selectivities obtained from the reactions of this type of nitrones are often lower than those formed from the reactions of 16a,b and analogous. As a part of these extensive studies several different alkenes have been applied in 1,3-DC reactions leading to optically active proline analogous,33 isoxazolidine nucleosides,32 and R-aminophosphonic acids.34 More recently Kibayashi et al. have extended these studies to the application of partially protected Ngulonofuranosyl nitrones in the synthesis of (+)-



Scheme 4

Scheme 5

negamycin and (-)-epinegamycin.38,39 They applied a protected gulonofuranosyl group a chiral auxiliary (Scheme 4). The nitrone 19, formed from the corresponding glucose oxime and methyl glyoxylate, exists as a mixture of the Z and E isomer and hence, the 1,3-DC reaction with allylamine 20 gives 21 in a 2:3 ratio of the trans and cis isomers. Similar observations have been reported by Vasella et al.31,33 Contrary to the poor cis/trans selectivity, the diastereofacial selectivity of the 1,3-DC reaction between 19 and 20 is high. This selectivity is determined after hydrolysis, benzylation, and reduction of the ester to give 22a,b in high optical purities. By further reactions of 22a and 22b, respectively, (+)-negamycin 23a and (-)-epinegamycin 23b are obtained. The chiral moiety of the nitrone can also be located at the carbon atom. Baggiolini et al. have used this approach in the total synthesis of 1R,25-dihydroxyergocalciferol (26), a molecule arising from the degradation of vitamin D3 in human liver and kidney.40 The nitrone 24 is obtained from the corresponding aldehyde, and the 1,3-DC reaction with methyl 3,3dimethylacrylate affords isoxazolidine endo-25 (Scheme 5). The reaction proceeds with a high degree of endo selectivity, but shows no diastereofacial selectivity. However, the two endo isomers are separated by chromatography and after several synthetic steps 26 is achieved. A similar synthetic sequence has been carried out to reach a related target molecule.41

Brandi et al. have studied the 1,3-DC reactions of chiral R,β-dialkoxynitrones with vinylphosphine oxides (eq 10).42 The reaction of optically active 27 with vinylphosphine oxide 28a gives a 65:14 mixture of the endo:exo isomers, along with 21% of the other regioisomer. The endo isomer is formed with a high diastereofacial selectivity of 94% de. By the application of the optically active vinylphosphine oxide 28b, the 1,3-DC reaction with 27 proceeds to form 29b with a high degree of endo selectivity and without


the appearance of the other regioisomer. The reaction also displays an excellent diastereofacial selectivity, since the product is obtained with 96% de. A racemate of nitrone 27 has been used in a 1,3DC reaction with vinyl ethers or esters 30 by DeShong et al.43 The reaction proceeds with high endo selectivity and diastereofacial selectivity to give rac31a in up to 100% de (Scheme 6). The product of Scheme 6


crotonate 33, the 1,3-DC product 34 is obtained in an endo:exo ratio of 10:1 and with a high diastereofacial induction of the endo isomer (eq 11). Other nitrones 35-37 in which the chiral moiety is located at the carbon atom have been applied in reactions with acryloyl or crotonoyl esters.46-48 Nitrones 35 and 36 offer poor discrimination in the 1,3DC reactions with benzyl crotonate as all four diastereomers are obtained in both reactions.47,48 The ribose-derived nitrone 37 is obtained in situ from the corresponding oxime by Michael addition to methyl acrylate.46 This nitrone reacts with another equivalent of methyl acrylate in a 1,3-DC reaction to give, in the best case, a 44:21:0:0 ratio of the four possible diastereomers.

Mukai et al. have applied a chiral tricarbonyl(η6arene)chromium(0)-derived nitrone 39 in the 1,3-DC reaction with various alkenes, such as styrene 10 (eq 12).49,50 The analogous nonmetallic nitrone 38 is used the reaction has been utilized in the synthesis of the amino sugar (()-daunosamine. The preferred formation of rac-31a in the 1,3-DC of rac-27 with 30, has been explained by assuming that conformation A (Scheme 6) is the reactive conformation of the reaction. According to Felkin-Anh A is expected to be the more reactive conformer because as the alkene approaches the sp2-hybridized carbon atom it avoids interaction with the bulky R2 substituent.43 Nitrones similar to 27 have also been applied to give >90% of one isoxazolidine isomer in the 1,3-DC reaction with methyl crotonate.44 Saito et al. have developed a tartaric acid derived chiral nitrone 32.45a In a reaction of 32 with methyl

in a reference reaction with 10, giving isoxazolidine 40, with an endo:exo ratio of 82:18. By the application of nitrone 39 in the 1,3-DC reaction with 10 the endo:exo selectivity changed significantly to give exo41 as the only observable product. The tricarbonylchromium moiety effectively shields one face of the nitrone, leading to high diastereofacial selectivity of


the reaction. The product exo-41 is obtained with 96-98% de. The chiral moiety in a nitrone can be attached to both the carbon and nitrogen atoms at the same time in cyclic nitrones. The cyclic structure offers a more rigid conformation than acyclic compounds, leading to a more efficient shielding of one of the nitrone faces, when the chirality is located in the ring. Furthermore, in this approach the possible E/Z interconversion of the nitrone is avoided. The first application of an optically active cyclic nitrone in 1,3-DC reactions was reported by Vasella et al. in 198551 and during the last 5 years a number of successful reactions of optically active cyclic nitrones have been published.52-66 Brandi et al. have studied the application of the L-tartaric acid derived nitrones 42a-d.55-57,63,65,66 Nitrone 42e shows a high degree of chiral discrimination in the 1,3-DC reaction with methylenecyclopropane at rt, leading to one regioisomer in a yield of 75% with a de of 82%.56 This approach has successfully been applied in the synthesis of optically active hydroxylated indolizidines.55,56,61,63 Nitrone 42a which was developed by Petrini and co-workers65 has also been applied by others in a highly diastereoselective 1,3-DC reaction with a silyl-protected allylic alcohol.61 Two similar nitrones 43 and 44, synthesized from L-malic acid and L-prolinol, respectively, have been subjected to 1,3DC reactions with various alkenes, such as methylenecyclopropane, showing moderate to excellent diastereofacial selectivities.62,64,66 Saito et al. applied nitrone 45 in reactions with fumaric and maleic acid derivatives at 70 °C in benzene and all reactions proceeded with complete regio- and diastereoselectivity.52

In 1994, Oppolzer et al. applied a chiral cyclic nitrone in the synthesis of (-)-allosedamine Scheme 7.60 They used the well-known chiral sultam 46 as the chiral auxiliary.67,68 The enantiomerically pure nitrone 48 is synthesized in an ingenious manner from 47. The enolate of 47, generated upon base treatment, attacks 1-chloro-1-nitrosocyclohexane at the nitrogen atom and subsequent elimination of chloride yields a nitrone. Addition of aqueous HCl hydrolyzes the acetal as well as the intermediate acyclic nitrone to give the cyclic nitrone 48 by condensation between the aldehyde and the hydroxyl-

Chemical Reviews, 1998, Vol. 98, No. 2 871 Scheme 7

amine moiety generated this way. The nitrone takes part in a 1,3-DC reaction with styrene 10 and the reaction proceeds with absolute exo specificity. The product 49 is obtained with a de of 93%. Two further reaction steps yield the piperidine alkaloid (-)allosedamine 50 in an overall yield of 21%. Finally, three other types of chiral cyclic nitrones 51-53 have been described. They are all characterized by having an oxygen atom in the ring and by providing excellent selectivities in 1,3-DC reactions with alkenes. Langlois et al. applied nitrone 51 in the synthesis of (-)-carbovir, a potential agent in treating AIDS.58,59,69 The 1,3-DC reaction between cyclopentadiene and 51 proceeds at 40 °C with high regio- and diastereoselectivity and 54 is the only product isolated. In the proceeding synthetic steps toward (-)-carbovir the camphor skeleton is recovered. From L-menthone and an in situ generated nitrosoketene, nitrone 52, was obtained by Katagiri et al.54,70 In a reaction with allyltrimethylsilane at 40 °C and at a pressure of 800 MPa, isoxazolidine 55 was obtained as the sole product isomer in 90% yield. After hydrolysis and hydrogenolysis, enantiomerically pure R-amino acids were synthesized and L-menthone was recovered. Tamura et al. prepared nitrone 53 which was subjected to react with various



alkenes.53 In the reaction between 53 and 2-methylpropene, isoxazolidine 56 is formed in 87% yield as a single isomer.

3.2. Chiral Alkenes For 1,3-DC reactions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is localized as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently applied in asymmetric 1,3DC reactions with nitrones. The alkenes employed can be divided into three main groups: (i) chiral allylic alcohols, (ii) chiral allylic amines, mostly β,γunsaturated amino acid derivatives, and (iii) chiral vinyl sulfoxides or vinylphosphine oxides. Examples of the application of chiral auxiliaries with the chiral center localized two or more bonds apart from the alkene, will also be mentioned. Kibayashi et al. have used enantiomerically pure allylic ethers/alcohols obtained from natural sources in 1,3-DC reactions with nitrones.71-75 They have applied this approach in the synthesis of optically active alkaloids containing a piperidine ring such as (+)-monomorine I,71,74 (+)-coniine,72 and (-)-oncinotine.75 Nitrone 57 reacts with allyl ether 58 to give selectively the exo products 59 and 60, and only minor amounts of the endo isomers (eq 13).72 The

best diastereofacial selectivities are obtained when the substituents R1 is either benzyl or SiPh2t-Bu, and when R2 is i-Pr or t-Bu. The mechanism for the addition of the nitrone to the chiral alkene was briefly discussed.71,72,74 From these substrates, the products exo-59 and exo-60 are obtained with a preference for exo-59 in up to 90% de. Related investigations have been performed by others.76,77 Saito et al. have developed a variety of tartaric acid derivatives, including C2-symmetrical chiral alkenes such as 61.45 The 1,3-DC reaction between 61 and 57 gives primarily endo-62 (eq 14). The diastereofacial selectivity of the reaction is excellent, as endo62 is obtained with a de >98%. Other cyclic and acyclic nitrones have been employed in reactions with 61, and in all cases, moderate to excellent endo:exo selectivities and excellent diastereofacial selectivities are obtained.45 Three other research groups have been applying various γ-hydroxylated R,β-unsaturated carbonyl compounds in related reactions with

nitrones;78-80 however, the selectivities were somewhat lower than those obtained by Saito et al.45 Chiral allylic alcohols may also be cyclic, such as the sugar lactones used by Chmielewski et al.81-83 C-Methylnitrones 63 approach 64 in an endo-selective manner to the face of the alkene anti to the substituents of the lactone ring. In this reaction endo-65 is obtained as the sole product (eq 15).

Feringa et al. have used a similar principle by employing chiral furanones (butenolides). In this case, however, the asymmetry is obtained from a chiral auxiliary. The chiral 4-substituted butenolide 67 is prepared from 66 and menthol (Scheme 8).84,85 The single diastereomer 67 is obtained by crystallization and epimerization of the other diastereomer, as the amount of 67 in solution decreases. In the 1,3-DC reaction of 67 with C,N-diphenylnitrone 68, one face of the alkene is selectively shielded by the menthol moiety, leading exclusively to the anti adduct 69 as a 65:35 mixture of the exo and endo isomers, respectively. The alkene 67 has been used in several highly diastereoselective 1,3-DC reactions with other types of 1,3-dipoles (vide infra). Reed and Hegedus have applied optically pure 4,4disubsituted butenolides in a 1,3-DC reaction with 1-pyrroline 1-oxide in a highly selective reaction giving the exo isomer with >97% de.86 Similarly, other derivatives of chiral cyclic R,βunsaturated carbonyl compounds have been subjected to 1,3-DC reactions with nitrones.30,87-90 Langlois et al. have applied R,β-unsaturated γ-lactams

Asymmetric 1,3-Dipolar Cycloaddition Reactions Scheme 8


trone 68.91,92 The 1,3-DC of 68 with the chiral oxazolidinone 75, proceeded to give endoa-76 and exoa-76 in a ratio of 70:30 (eq 18). Both product isomers arise from attack of the nitrone 68 to the face of the alkene 75 anti to the phenyl substituent. Four research groups have applied 1,3-DC reactions between nitrones and amino acid derived allylic amines 77 for natural product synthesis. The formaldehyde-derived nitrones 78 are used in 1,3-DC reactions to give the isoxazolidines 79 and 80 (Scheme 9).93-97 However, only by the contemporary use of a Scheme 9

derived from (S)-pyroglutaminol, such as 70, in the 1,3-DC with N-benzylnitrone 71 (eq 16).87 One of the 1,3-DC product isomers, compound 72 was isolated in 75% yield, whereas only 5% and 3% of two other isomers were obtained.

Paton et al. have applied the bicyclic lactone levoglucosenone 73 in the reaction with various different 1,3-dipoles.88,89 In the reaction with C,Ndiphenylnitrone 68 the reaction proceeds to give 74 as the only observable product (eq 17).

In two recent papers the use of exo-cyclic alkenes have been applied in reactions with C,N-diphenylni-

chiral nitrone were satisfying selectivities obtained. Whitney et al. applied a ribose derivative as the chiral substituent and in the reaction with 77 the products 79 and 80 could be obtained in a ratio of 1:19.94-96 The major product 80 obtained in this reaction has been applied in the total synthesis of acivicin 81, a naturally occurring antitumor antibiotic.95,96 Naito et al. have applied a similar amino acid derived alkene in the synthesis of tetrahydropseudodistomin.98 Another type of chiral alkenes applied in 1,3-DC reactions with nitrones are vinyl groups attached to chiral heteroatoms such as phosphine oxides and sulfine oxides. Brandi et al. have used chiral vinylphosphine oxide derivatives as alkenes in 1,3-DC reactions with chiral nitrones.99,100 This group also studied reactions of achiral nitrones with chiral vinylphosphine oxide derivatives. By using this type of substrates high endo/exo selectivities were obtained and in reactions involving optically pure vinylphosphine oxides diastereofacial selectivities of up to 42% de were obtained.99,100 Chiral vinyl sulfoxides have also been applied in 1,3-DC reactions.101-105 These substrates were first used successfully in the 1,3-DC reaction by Koizumi et al. in 1982.103,104 In the 1,3-DC reaction of an (R)-p-tolyl


vinyl sulfoxide and C,N-diphenylnitrone high selectivities were obtained. Louis and Hootele´ have studied the 1,3-DC reactions of vinyl sulfoxides 82 in the 1,3-DC reaction with the cyclic nitrone 57 (Scheme 10).101,105 The reactions proceed with absoScheme 10

lute exo selectivity, and, especially when the substituent at the (Z)-alkene is phenyl a high de of 96% is obtained. In the case where R ) Me (de ) 82%) the product 83 has been applied in the synthesis of the natural product (+)-sedridine 84. Finally, some examples of 1,3-DC reactions of nitrones with chiral alkenes, in which a chiral auxiliary directs the stereochemical outcome of the reaction, will be presented.106 The first example implies chiral vinyl ethers. The selectivities obtained for most derivatives are low. However, using alkene 85 and the cyclic nitrone 57, the reaction proceeds with high selectivity (Scheme 11). The endo:exo Scheme 11

selectivity is not given in this communication by Carruthers et al.,107 but this is of minor importance for the final outcome of this work, since one of the chiral centers was destroyed in the conversion of 86 into the final product 87. The chiral auxiliary can by recovered in this reaction sequence and 87 was obtained with an optical purity of >95% ee. Several attempts to control the regio- and stereoselectivity of reactions of nitrones with acrylates and other R,β-unsaturated carbonyl compounds have been made by using chiral auxiliaries.67,108-113 Acrylates of Oppolzer’s chiral sultam 8968 have successfully been applied in asymmetric Diels-Alder reactions and to a smaller extent these derivatives have also


been used in 1,3-DC reactions of nitrones.108,110,113 Recently, Tejero et al. studied reactions of C-(2thiazolyl)nitrone 88 with various chiral acrylates.113 In contrast to reactions of simple acryl esters, the reaction of 88 with 89 proceeded with complete regioselectivity to give the 3,5-disubstituted isoxazolidine 90 (eq 19) The product was obtained with complete endo selectivity and with a diastereofacial selectivity of 56% de. In a related reaction using a sterically crowded nitrone high selectivity has been obtained.108

Tejero et al. also studied the use of other auxiliaries such as 91 and 92 in the 1,3-DC reaction. However, application of 91 led to a very low selectivity. In the reaction between 88 and 92 no conversion was obtained even in refluxing toluene.113 On the other hand, Murahashi et al. were able to obtain conversion in the reaction of 92 with 1-pyrroline 1-oxide.110 Relatively poor selectivities were observed for this reaction, but by the addition of ZnI2 selectivities were dramatically improved (vide infra). Using the same type of cyclic nitrones Olsson et al. observed a low endo/exo selectivity, but excellent diastereofacial discrimination in the reaction with the camphorderived chiral acrylate 93.111 Finally, it should be mentioned that application of the optically active 9-anthrylcarbinol derivative 94 in a reaction with 1-pyrroline 1-oxide gave rise to a complex mixture of regioisomers and diastereomers.109


3.3. Intramolecular Reactions Since the pioneering work by LeBel114,115 intramolecular 1,3-DC reactions of alkenylnitrones have found broad application in organic synthesis.22,116 Intramolecular 1,3-DC reactions have several advantages over the corresponding intermolecular reactions. Due to entropy factors the activation barrier for the reaction is lower, allowing for lower reaction temperatures and for the use of dipoles and dipolarophiles of lower reactivity. The degree of spatial freedom in the transition state of an intramolecular reaction is, of course, limited compared with the intermolecular reactions. Hence, a higher degree of regioselectivity, endo/exo selectivity, and diastereofacial selectivity is normally observed in intramolecular 1,3-DC reactions. The intramolecular reactions of nitrones bound to alkenes can be divided into two types. The alkene part may be linked to the carbon atom or to the nitrogen atom of the nitrone. The majority of the reported intramolecular 1,3-DC reactions are those in which the alkene part is linked to the carbon atom of the nitrone. This type of reaction gives rise to two regioisomers, in which the isoxazolidine product formed is either a bicyclo[x,3,0] or a bicyclo[x,2,1] compound A and B (Scheme 12). The most frequently observed product is the bicyclo[x,3,0] compound. As for intermolecular 1,3-DC reactions, the endo and exo isomers of each of the regioisomers can be formed in intramolecular reactions. In most cases the exo isomer is favored for sterical reasons. Scheme 12

This chapter is organized on the basis of the structure of the nitrones and the nature of the reactions. Reactions in which the alkene is connected to the nitrone carbon atom will be presented. These reactions are further divided in reactions (i) in which the chirality is located in the resulting bicyclic isoxazolidine, (ii) similar reactions of oximes, (iii) reactions involving sugar derivatives as starting material, (iv) reactions in which the chirality is located outside the resulting bicyclic isoxazolidine, (v) reactions of cyclic alkenes leading to tricyclic products, and (vi) reactions in which the chiral group is located at the nitrone nitrogen atom. Finally, (vii) reactions in which the alkene is connected to the nitrone nitrogen atom will be described. Several groups have reported intramolecular reactions of 5-alkenylnitrones in which the chiral center


is located on a carbon atom in the alkene-nitrone link, leading to 3-oxa-2-azabicyclo[3.3.0]octanes and heteroanalogues.115,117-125 Aurich et al. have made extensive studies on reactions involving alkenylnitrones 96, formed in situ from 5-alkenylaldehydes 95.117,119,121,122,124 The substituent located vicinal to the nitrone carbon atom, directing the facial selectivity of the reaction is most frequently alkyl, benzyl, or phenyl, but occasionally other oxygen or nitrogen substituents have been applied.118,123 The reaction of 95 proceeds in CH2Cl2 or Et2O at 0 °C to rt to give, most frequently, only one (97) out of four possible diastereomers (Scheme 13). As previously mentioned the exo diastereomer is generally favored in intramolecular reactions of this type, and the excellent diastereofacial selectivity is proposed to be due to the sterically favored equatorial position of the R1 substituent in intermediate 96a compared to 96b.119,121,124 In a similar manner optically active 6-alkenylnitrones and heteroanalogues have been applied in the synthesis of bicyclo[4.3.0] derivatives.90,114,126,127 Fukumoto et al. used this type of reaction in the synthesis of a 1β-methylcarbapenem antibiotic.90,127 Baldoli et al. utilized the optical active tricarbonylchromium(0)-derived 6-alkenylnitrone 98 (eq 20).128 The Cr(CO)3 moiety offers an effective asymmetrical induction and the [4,3,0] bicyclic isoxazolidine 99 is formed as the single stereoisomer. The formation of optically pure [3.2.0]-bicycles from 4-alkenylnitrone has also been reported.126

The chiral center which controls the diastereofacial selectivity of the reaction may also be located outside the resulting bicyclic isoxazolidine (eq 21).129,130 The double bond of 100 is generated in situ and undergoes a 1,3-DC reaction with the nitrone moiety of the molecule in refluxing CCl4 to form 101 (eq 21). In the present reaction the exo-cyclic chiral center directs the selectivity completely, since only one product isomer arises. However, application of other derivatives of starting materials in some cases led to poor diastereofacial selectivities.


Gothelf and Jørgensen Scheme 15

In addition to the above-described reactions a number of alkenylnitrones derived from sugar derivatives have been applied in intramolecular 1,3DC reactions.131-146 The reactions leading to bicyclo[3.3.0] compounds will be described first. Bernet and Vasella were the first to perform extensive studies in this field.138-140 Glucose derivative 102 was converted into the 5-alkenyl aldehyde 103 and upon treatment with methylhydroxylamine, the resulting nitrone underwent intramolecular 1,3-DC reaction to give 104 as the only diastereomer in good yields (Scheme 14).140 Mannose and galactose were subScheme 14

jected to the same procedure, giving rise to the formation of compounds similar to 104 with a high degree of selectivity.138,139 This approach has been applied in the synthesis of a prostaglandin precursor,144 an R-mannosidase inhibitor147 and other optically active hydroxylated cyclopentanes.141,143 Furthermore, a modified method has been applied for the synthesis of isoxazolidine nucleosides.148,149 In a similar way sugar-derived 6-alkenylnitrones have been applied in intramolecular 1,3-DC reactions to form [4,3,0]-bicyclic products. Wightman et al. utilized this approach in the synthesis of (-)-shikimic acid,145 and Farr et al. applied a less selective reaction for the preparation of amino inositol derivatives.146 Carbohydrate-derived alkenylnitrones have been used in an alternative manner for the synthesis of oxepanes.133-135,137,142,150 Shing et al. found that upon treatment of the glucose-derived aldehyde 105 with

methylhydroxylamine, the resulting nitrone reacted to give a mixture of the oxepane 107a and tetrahydropyrane 107b, as pure diastereomers (Scheme 15).132,142 In this case the transition state 106a, in which the alkene termini is attached to the nitrone carbon atom is preferred over transition state 106b and the desired oxepane 107a is obtained as the major product. However, the regioselectivity is strongly controlled by the configuration of the C-3 of the furanose ring. Earlier studies by Bhattacharjya et al. have also shown that the introduction of a methyl substituent at the C-3 position of the furanose ring dramatically alters the regioselectivity.133,134,137 An alternative and elegant approach to [3.3.0]bicyclic isoxazolidines from alkenyloximes was developed by Grigg et al.151 and applied in asymmetric reactions by Hassner et al.152-155 and recently also by others.156 The optically active L-serine derived oxime 108 is proposed to be in a thermal tautomeric equilibrium with the nitrone tautomer 109, which undergoes an intramolecular 1,3-DC reaction to form the product 110 in 80% yield as the sole stereoisomer (Scheme 16).155 If the alkene moiety of the alkenylnitrone is incorporated into a cyclic compound, complex tricyclic compounds are formed in the intramolecular 1,3-DC reaction. Baggiolini et al. applied this approach in an ingenious synthesis of D-biotin 113.157 The cysteine-derived alkenylnitrone 111, which as an exception is stable at rt, was able to form the isoxazolidine 112 in a satisfying yield as the single diastereomer


(Scheme 17). Further synthetic steps led to the desired optically pure target molecule 113. Other research groups have applied cyclic alkenes in intramolecular nitrone 1,3-DC reactions, especially in the formation of 2-oxa-3-azatricyclo[5.3.1.04,11] compounds.158-163 Scheme 17


proach in the synthesis of the alkaloid (-)-indolizidine 209B 122.156,167 The alkenylnitrone 119, is obtained from the chiral hydroxylamine 118, and an aldehyde. In the intramolecular 1,3-DC reaction 120 is formed as the only product isomer (Scheme 19). The diastereofacial selectivity is controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group is in a pseudoequatorial position, as indicated in 119. Further transformation of 121 leads to the desired product 122. Scheme 19

The chiral center controlling the diastereofacial selectivity of the reaction may also be located at the nitrogen atom of the nitrone.136,164-166 Baldwin et al. employed the previously described 1-phenylethylhydroxylamine 6 as the chiral group. Alkenylnitrone 115, generated in situ from the achiral aldehyde 114, undergoes an intramolecular 1,3-DC reaction to give 116 with a de of 94% (Scheme 18).164 Further reactions were performed to give 117, which was used as a model compound for a planned asymmetric synthesis of the alkaloid pretazettine. L-Acosamine and L-daunosamine have also been synthesized using 6 as the chiral fragment.165,166 In all the above-described intramolecular 1,3-DC reactions the alkene moieties have been linked to the nitrone via the nitrone carbon atom. However, in a limited number of contributions the utilization of optically active alkenylnitrones, in which the alkene is connected to the nitrone nitrogen atom, is reported.167-172 Holmes et al. have used this ap-

A new approach to optically active N-linked alkenylnitrones was developed by Frederickson et al.171,172 The intermediate nitrone 125 was formed by attack of the nitrogen atom of oxime 123 to divinyl sulfone 124 (Scheme 20). The 1,3-DC reaction is proposed to proceed via 125 to yield the bicyclic isoxazolidine 126 as the sole diastereomer. Oximes derived from D-galactose and D-ribose have been applied in analo-

878 Chemical Reviews, 1998, Vol. 98, No. 2 Scheme 20


Contrary to the broad application of catalysts in asymmetric carbo- and hetero-Diels-Alder reactions,173 the use of metal catalysts in asymmetric 1,3DC reaction between alkenes and nitrones remained an unexplored area until recently. Kanemasa et al. did important pioneering work in this field, although the reactions performed were racemic. The first contribution was published in 1992 and describes the impact of ZnI2, TiCl(Oi-Pr)3 and TiCl2(Oi-Pr)2 upon the 1,3-DC reaction between nitrone 127 and enone 128174 (eq 22). The reaction

presence of Mg(II) salts, ZnBr2, TiCl2(Oi-Pr)2, or BF3‚ Et2O.175,176 The reaction of nitrone 130 with allyl alcohol at rt yields a cis:trans mixture of 44:56 of the product isoxazolidine 132. The lack of selectivity is presumed to be caused by the Z/E isomerization of 130. In the presence of 100 mol % MgBr2‚Et2O, the reaction of 130 with allyl alcohol proceeds at approximately the same rate, but with a high selectivity as rac-cis-132 is obtained as the only product (Scheme 21). The selectivity of the reaction is explained by a favored chelation of the (Z)-nitrone and concomitant coordination of allyl alcohol to MgBr2, as outlined in 131.176 A related, but asymmetric work appeared in 1993 from Murahashi et al.110 They used cyclic nitrones such as 57 and the chiral phenylalanine derived alkene 133 (eq 23). The 1,3-DC reaction proceeds at

proceeds at 80 °C in the absence of a metal complex to give 129 in an endo:exo ratio of 40:60. Upon addition of ZnCl2, the reaction proceeds at rt, but a reaction time of 52 h is required to give a yield comparable to that of the uncatalyzed reaction. The addition of ZnCl2 has a rather dramatic impact on the endo:exo ratio as the endo isomer is now formed predominantly. In the presence of 1 equiv of Ti(OiPr)2Cl2 the reaction proceeds at 0 °C to give a yield of 50% after 32 h and in this reaction the rac-endo129 is formed as the only isomer. These early results indicate that a certain degree of rate acceleration can be obtained, at least by the addition of stoichiometric amounts of Lewis acids and that the additives have a high impact on the endo/exo selectivity of the reaction. In extension of this work Kanemasa et al. studied reactions of allylic alcohols with nitrones in the

35 °C in the absence of a metal complex. The endo: exo ratio of the reaction is 82:18, and the diastereofacial selectivity of endo-134 is 18% de. By the addition of 150 mol % of ZnI2, the endo:exo ratio is improved to 89:11, and most remarkably the diastereofacial selectivity is improved to 92% de giving endo-135 as the major isomer. However, the addition of ZnI2 decreases the reaction rate as a reaction time of 48 h is needed to obtain a yield of 82%. Tamura et al. have reported a metal-catalyzed tandem transesterification-intramolecular 1,3-DC reaction,177,178 which only proceeds in the presence of Ti(i-PrO)4 or TiCl4. The reaction of the methyl glyoxylate derived nitrone 136 and an optically active (Z)-alkene, such as 137, takes place at rt in the presence of 10% TiCl4, presumably via intermediate 138, to afford the product 139 quantitatively with a high de (Scheme 22). In the absence of titanium salts

gous reactions also proceeding with high diastereoselectivity.

3.4. Metal-Catalyzed Reactions



Scheme 22

Scheme 24

and at elevated temperatures, an intermolecular 1,3DC reaction occurs, and it is therefore obvious that TiCl4 catalyzes the transesterfication; however, the role of TiCl4 in the cycloaddition step is less obvious. In a recent work by Katagiri et al. the application of BF3‚Et2O as catalyst for the reaction of nitrone 52 with allylsilane rac-140 was described (Scheme 23).54,70 The reaction between 52 and 2 equiv of the racemic alkene 140 proceeds only in the presence of 1 equiv og BF3‚Et2O at rt; hence, there is no doubt about the catalytical effect of the Lewis acid. The product of the reaction, 142, is formed in 69% yield as the sole stereoisomer and what is especially noteworthy is that only the S isomer of 140 reacts with 52. The kinetic resolution of rac-140 is proposed to be due to a transition state 141, in which the sterical arrangement of SiMe3 and BF3 only allows for the S isomer of 140 to undergo 1,3-DC reaction with 52.70 Trombini et al. have described the formal 1,3-DC reaction of 2-[(trimethylsilyl)oxy]furan 143 with chiral nitrones 144 catalyzed by various metal complexes (Scheme 24).179-181 The reaction proceeds in the presence of stoichiometric amounts of an activator, such as (+)- or (-)-(Ipc)2BOTf. In both cases 145a is obtained as the major stereoisomer with a high endo selectivity and a diastereofacial selectivity of up to 96% de.179 Since, the same diastereomer is obtained in similar selectivities from both (+)- and (-)(Ipc)2BOTf, the face selection is controlled by the chiral substrate 144. The reaction is, however, assumed to proceed via a stepwise mechanism (Scheme 24). By the use of stoichiometric amounts of boron, aluminum, zinc, or titanium catalysts the reaction of 143 with 144, gives the allyl cation 146. This intermediate cyclizes (route A) to give 147 and

after hydrolysis 145 is obtained. When the above catalysts are used in catalytic amounts or when TMSOTf is used as the catalyst, the reaction proceeds from 146 via route B to give the butenolide 148 as the product. The 1,3-DC product 145 was obtained after treatment with flouride. A catalytic cycle was proposed for this approach.179 Especially, TMSOTf is an effective catalyst for the reaction when used in a catalytic amount; however, by this method a mixture of all for diatereromers of 145 was obtained. In the above-described reactions the asymmetry was induced by chiral substituent in the starting material; however, in 1994 the first two, and quiet different, approaches to asymmetric 1,3-DC reactions of achiral alkenes with achiral nitrones catalyzed by chiral metal complexes appeared.182,183 Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-DC reaction of a nitrone with alkenes.183 Their approach involves C,N-diphenylnitrone 68 and ketene acetals 149. This reaction of an electron-rich alkene is controlled by the LUMOnitrone-HOMOalkene interaction. They found that coordination of the nitrone to

Scheme 23


a Lewis acid strongly accelerated the 1,3-DC reaction with ketene acetals. To obtain asymmetric induction the amino acid derived chiral oxazaborolidines which have successfully been applied in asymmetric DielsAlder reactions184,185 were tested as catalysts for the 1,3-DC reaction. The reactions of 68 with 149a,b, catalyzed by 20 mol % of oxazaborolidinone such as 150a,b, are outlined in eq 24. The reaction is carried out at -78 °C and gives the C-3, C-4 cis isomer 151b as the only diastereomer of the product when R1 ) Me (149b). In some reactions good enantioselectivities are induced by the catalysts, thus, 151a is obtained with an optical purity of 74% ee, and isoxazolidine 151b with an ee of 62%.

In an extension of this work Scheeren et al. studied various derivatives of N-tosyloxazaborolidinones as catalysts for the 1,3-DC reaction of 68 with 149b.186 The addition of a cosolvent appeared to be of major importance. Catalyst 150b is synthesized from the corresponding amino acid and BH3‚THF; hence, THF is present as a cosolvent. In this reaction (-)-151b is obtained with 62% ee. If the catalyst is synthesized from the amino acid and BH3‚SMe2, and diphenyl ether is added, a remarkable reversal of the enantioselectivity of the reaction occurs, since (+)151b is now obtained as the major isomer. Furthermore the ee in this approach is improved to be 79%. In a very recent work Scheeren et al. have applied cyclic and acyclic vinyl ethers in the oxazaborolidinone catalyzed 1,3-DC reaction with nitrones.187 The reaction between nitrone 152 and 2,3-dihydrofuran 153 was catalyzed by 20 mol % 154 to give the product 155 in 56% yield as the sole diastereomer; however, the ee was 38% (eq 25).


Later in 1994 a different approach to a 1,3-DC reaction between alkenes and nitrones catalyzed by a chiral metal catalyst appeared.182,188 The reaction between 3-N-alk-2-enoyloxazolidinones 156 and nitrone 157 need elevated temperatures to proceed in the absence of a catalyst (eq 26). However, in the

presence of 10 mol % of the TADDOLate-TiCl2 catalyst 159a the reaction proceeds at 0 °C to rt in toluene/petroleum ether. This type of catalysts has successfully been applied in a number of asymmetric reactions, especially the Diels-Alder reaction.189-191 It is proposed that the rate acceleration is achieved via a bidentate coordination of 156 to the titanium catalyst. By this coordination the energy of the LUMOalkene is significantly decreased compared to the free alkene and this change of the LUMOalkene energy increases the rate of the reaction with the relatively electron-rich nitrone 157. Hence, compared to the work described above by Scheeren et al. in which a nitrone is activated by a metal catalyst for reaction with an electron-rich alkene, the approach in the present work employ catalyst-induced activation of the alkene part and is controlled by the opposite electron demand. In the presence of catalyst 159a the reaction proceeded to give the product 158 in high yield with an endo:exo ratio of up to 10:90 (R1 ) Me, R2 ) Ph). Enantioselectivities of 60% and 62% ee of the endo and exo isomers, respectively, were obtained. The optical purity of the major exo isomer was improved to 95% ee by recrystallization. Catalyst 159b induced a lower enantioselectivity, but, the endo:exo ratio was improved to 5:95%.

In an extension of this work the impact of various achiral and chiral Cu(II) and Mg(II) complexes on the reaction was introduced. Application of 10 mol % the achiral MgI2-phenanthroline catalyst 160 and an additional amount of I2, strongly accelerated the reaction and also led to a high degree of endo selectivity (eq 26).20 The reaction of the valin-derived alkene 162 and nitrone 157a,b was also catalyzed



in the presence 10 mol % of 160 as the catalyst and the reaction proceeded to give endo-163a as the sole product out of four possible in 99% yield (eq 27). To

obtain catalyst induced asymmetry in the Mg(II)catalyzed 1,3-DC reaction of achiral starting material, the chiral MgI2-bisoxazoline catalyst 161, was applied. In some entries the catalyst induced high endo selectivities and up to 82% ee (eq 26). On the basis of an X-ray structure of endo-163b, which contains a chiral center with a known configuration, the absolute structure of this product was determined.20 By deriving endo-163b and the corresponding derivative of endo-158 into the isopropyl esters the absolute configuration of the 1,3-DC products was determined.20,192 In connection with the work on the titaniumcatalyzed reactions an intermediate 164 consisting of the catalyst 159a and N-cinnamoyloxazolidinone was isolated as crystals and characterized by X-ray crystallography.193 The complex 164 was proposed to be an intermediate, not only in the 1,3-DC reaction of nitrones with alkenes, but probably also in the asymmetric TADDOLate-TiCl2-catalyzed DielsAlder reaction.193,194 Whether or not this complex actually represents the key intermediate in the reactions has been a subject of debate.194-197 DiMare et al. and Seebach et al. assumed that in intermediates similar to 164, neither of the alkene faces are shielded sufficiently to account for the high enantioselectivities frequently obtained in the TiCl2-TADDOLate-catalyzed Diels-Alder reaction.195,196 They proposed another intermediate in which the two chloride ligands are arranged cis to each other to be more reactive and to offer a more effective shielding of one of the faces of the alkene. In this cis intermediate one of the alkenoyloxazolidinone carbonyls is arranged trans to one of the chloride ligands and this is supposed to lead to a higher reactivity of this intermediate compared to 164 where both carbonyls are arranged trans to the TADDOLate oxygen atoms. However, for the 1,3-DC reaction experimental results have indicated that an intermediate in which the chloride (or tosylate) ligand(s) is located trans to the plane consisting of titanium and the two alkenoyloxazolidinone carbonyls is the most reactive one.192,197 In a recent work Seebach et al. suggested the Ti-TADDOLate-catalyzed Diels-Alder reaction

to proceed via a cationic intermediate in which one of the chloride ligands is dissociated from the catalyst.198 If one assumes that 164 represents a key intermediate in the 1,3-DC reaction between an N-alkenoyloxazolidinone and nitrone, the axial ligand (indicated by an arrow in 164) would be of major importance for the endo/exo selectivity of the reaction. Due to steric repulsion between the axial ligand and the C-phenyl substituent of nitrone 157b, the exo transition state 165 (please observe that the cinnamoyl fragment in 164 has been exchanged with a crotonyl fragment) is less favored as the bulkiness of the axial ligand (indicated by an arrow in 165) is increased.192

Experiments have shown that exchange of the chloride ligand in catalyst 159a with bulkier ligands such as bromide (159c) or triflate (159d) changes the endo:exo ratio of the reaction in (eq 26) from 10:90 to 64:36 and 82:18, respectively. Introduction of the bulky tosylato ligands in catalyst 159e to some extent decreases the activity of the catalyst since 50 mol % is necessary to obtain a fair conversion. However, the catalyst provided excellent endo selectivities of >90% de in eight reactions of various substrates and more notable enantioselectivities of 91-93% ee were obtained for several reactions of different substrates (eq 26).192


The Ti-TADDOLate-catalyzed 1,3-DC reactions have also been extended to include an acrylate derivative.199 In the absence of a catalyst, the reaction between nitrone 166 and acryloyloxazolidinone 167 proceeds to give a mixture of all regio- and diastereomers (eq 28). However, application of 10 mol % of Ti(OTs)2-TADDOLate 159e as catalyst for the reaction of various nitrones such as 166 with alkene 167 leads to complete regioselectivity and high endo selectivity in the reaction and the endo product 168 is obtained with 48-70% ee (eq 28).199

Seebach et al. have developed a number of polymerand dendrimer-bound TiCl2-TADDOLate catalysts derived from the TADDOLs 170, 171, and others.198 Application of 10 mol % of this type of catalysts in the reaction between alkene 156a and nitrone 157a led to endo:exo ratios between 18:82 and 8:92 and enantioselectivities of until 56% ee (eq 29). The

selectivities are thus slightly decreased compared to the similar reactions of the homogeneous catalysts.182,198 They also made a study of the relationship between the enantiomerically purity of the ligand of the homogeneous catalyst 172, and the products obtained in both the 1,3-DC reaction of 156a and 157a and in the Diels-Alder reaction of 156a with cyclopentadiene. Surprisingly, the 1,3-DC shows a linear relationship, whereas the Diels-Alder reaction shows a positive nonlinear relationship.198,200 Further development was made by Furukawa et al. by investigations of chiral complexes of palladium as catalysts for the reaction (eq 29).106 The cationic palladium catalysts were obtained from PdCl2, Ag-


BF3, and chiral (S)-BINAP derivatives 173a or 173b.

In the presence of 10 mol % of the catalyst the reaction of 156a and 157c proceeds in refluxing CHCl3 to give the products as a mixture of the endo and exo isomers (eq 29). Yields are satisfying and most remarkable enantioselectivity of up to 91% of the endo isomer is achieved. In a recent work the exo selectivity of the TiCl2TADDOLate-catalyzed 1,3-DC reaction was improved by the use of succinimide instead of oxazolidinone as auxiliary for the R,β-unsaturated carbonyl moiety.201 The succinimide derivatives 174a,b are more reactive toward the 1,3-DC reaction with 157a, and the reaction proceeds at rt in the absence of a catalyst, and after conversion of the unstable succinimide adduct into the amide derivative, the endo isomer of 175 is obtained as the major isomer. In the presence of TiCl2-TADDOLate catalyst 159a (5 mol %) the reaction of 174a with 157a proceeds at -20 to -10 °C to give 175 in an endo:exo ratio of 95 (eq 30). Additionally, the enantioselectivity of the reaction of 72% is also an improvement compared to the analogous reaction of the oxazolidinone derivative 156a. Similar improvements were obtained in reactions of other related nitrones with 174a,b.


Two independent research groups have developed an ytterbium-catalyzed 1,3-DC reaction. Kobayashi et al. utilized 20 mol % of complex 177 consisting of Yb(OTf)3-BINOL and trimethylpiperidine in the presence of MS 4 Å as the catalyst for the 1,3-DC reaction between alkene 156 (R1 ) Me) and nitrone 166 (R2 ) Bn, Ar ) Ph) (eq 31).202 In this reaction,


180a,b led to the proposed intermediate 181a,b. The product 182a is obtained in moderate yields of 1442%, however, with high ee’s of up to 95% of trans182a. Application of 180b as the nitrone in the reaction leads to higher yields of 182b (47-68%), high trans selectivities and up to 93% ee.

4. Nitronates Alkyl and silyl nitronates are in principle N-alkoxyand N-silyloxynitrones, but the asymmetric 1,3-DC reactions of this type of 1,3-dipoles are described in a separate part. Nitronates 183 can react with alkenes 184 in a 1,3-DC reaction to form N-alkoxyor N-silyloxyisoxazolidines 185 (Scheme 26).21 The Scheme 26

the nitrone is generated in situ from benzaldehyde and benzylhydroxylamine. The reaction proceeds to give the product 176 in 72% yield with a high endo: exo ratio of >99:98% ee. This type of tandem reaction has also been applied by Chattopadhyaya et al., who used 2′,3′-dideoxy-3′nitro-2′,3′-didehydrothymidine as the starting material.216



Scheme 30

5. Azomethine Ylides The 1,3-DC reaction of azomethine ylides 203 with alkenes 204 leads to the formation of the pyrrolidines 205 (eq 33). Azomethine ylides are unstable species

which have to be prepared in situ. A number of methods has been developed for the generation of azomethine ylides, such as proton abstraction from imine derivatives of R-amino acids, thermolysis or photolysis of aziridines, and dehydrohalogenation of imonium salts.217 The reaction of azomethine ylides with alkenes has been investigated from a theoretical point of view in order to understand the reaction course, selectivity, and influence of Lewis acids on the reaction.80,84,218 Kanemasa et al. have studied the reaction of lithium (Z)-enolates derived from N-alkylideneglycinates with R,β-unsaturated esters by theoretical calculations using the MNDO and PM3 procedures.218 The reaction was proposed to proceed by a stepwise mechanism via an intermediate formation of a Michael adduct as outlined by the reaction path shown in Scheme 30. The initial step in the reaction outlined in Scheme 30 is an anti-selective carbon-carbon bond formation by a Michael addition process leading to C via transition state B. The second step takes place via transition state D which is a Mannich-type reaction, leading to the 1,3-DC product E.218 The energy differences between the transition states B and D were calculated to depend on the steric hindrance caused by the alkylidene moiety R4 as the bulky

alkylidene substituents prefer the formation of Michael adducts, while small ones prefer the 1,3-DC products. The energy barrier for the step leading to the 1,3DC product E from the Michael adduct is calculated to be in the range 9.2-28.5 kcal mol-1, depending on the substituents and the calculation method.218 The reaction of 5-(R)-menthyloxy-2(5H)-furanone with an N-benzyl-R-ethoxycarbonyl-substituted ylide was investigated by a FMO analysis using AM1 calculations.84 On the basis of the FMOs it was supposed that the R-ester carbon atom of the ethoxycarbonyl azomethine ylide reacts with the β-enone carbon atom of the alkene, and that the reaction is HOMOdipole-LUMOalkene-controlled.84 Annunziata et al. have used a series of PM3 and ab initio calculations to locate the transition state for the reaction of the simplest azomethine ylide (CH2NHCH2) with ethylene.80 The transition state was calculated by the ab initio calculations at a RHF/3-21G* level and on the basis of the calculated bond length (2.479 Å) of the carbon-carbon bond in the transition state, it was claimed that the reaction proceeds via an early transition state. Furthermore, the favored endo approach for the unsymmetrical substituted alkene to the azomethine ylide was found to be due to steric reasons as the distance between the ethyl hydrogen atoms and the azomethine hydrogen atoms was calculated to be relatively short (2.45 Å).

5.1. Chiral Azomethine Ylides In 1985 Padwa et al. published the first diastereofacial selective 1,3-DC reaction of chiral azomethine ylides with alkenes leading to optically active products (eq 34).219 In the 1,3-DC reaction of the azomethine ylide precursor 206a with 1-nitro-2-[3,4-(methylenedioxy)phenyl]ethene 207, the product 208a was obtained with 20% de, while 206b gave a de of 60%.219 To account for the diastereoselectivity, two different



DC reaction, as both the exo and endo products now are formed with excellent de’s (>95%).220 The reaction has been further improved by introducing a menthyl ester as the W substituent in 210.221 Using this chiral azomethyl ylide, only the exo product was obtained with a de >95%. The chiral template for the azomethine ylide outlined in Scheme 31 has been further developed to a chiral cyclic one by Harwood et al (Scheme 32).223-232 The chiral azomethine precursor 213 Scheme 32

conformations of the azomethine ylide were considered 209a,b. The approach of the alkene toward

209a is to the face of the azomethine ylide anti to the phenyl group, while anti attack in 209b results in an approach of the alkene to the opposite face of the dipole. It was argued that since the groups bound to the nitrogen atom in the azomethine ylide are similar both in size and electronic makeup, the excess of diastereoselectivity was small.219 In a series of papers Husson et al. have investigated the 1,3-DC reaction of electron-deficient alkenes with optically active azomethine ylides derived from mainly (-)-N-(cyanomethyl)-4-phenyl-1,3-oxazolidine 210, prepared in one step from (R)-(-)phenylglycinol (Scheme 31).220-222 In the reaction of Scheme 31

211 (W ) CN) with N-phenylmaleimide four adducts were isolated with 41% yield of the major diastereomer, while in the reaction of 211 (W ) CO2Et) two isomers were formed in nearly equal amounts. It is interesting to note that moving the phenyl substituent in 210 from position 4 to 5 leads to a significant improvement of the diastereoselectivity in the 1,3-

reacts with an aldehyde, mainly formaldehyde (R3 ) H), under formation of the azomethine ylide 214 which then reacts with an alkene, having electronwithdrawing substituents to give the 1,3-DC product 215. Removal of the chiral template in 215 leads to the formation of substituted proline derivatives. Reaction of 214 (R1 ) Ph, R2 ) R3 ) H) with maleimides leads to the formation of both the endo- and exo-cycloaddition products 216 and 217, respectively, with the former product in excess (Scheme 32).230 Changing to maleic anhydride as the alkene leads to the formation of the endo isomer as the sole product. The reaction of 214 (R3 ) Ph) with N-methylmaleimide leads to four products, the two endo- and two exo isomers, with a slight excess of the former. The preferred endo isomer is obtained from both the syn and anti orientations, respectively, of the phenyl substituent R3 relative to the chiral center in 214. In the reaction of 214 (R1 ) Ph, R2 ) i-Pr) with N-phenyl- or N-methylmaleimides the endo:exo ratio of the 1,3-DC product was improved.231 The presence of a Lewis acids, such as MgBr2‚Et2O, leads to an improvement of the yield of the 1,3-DC reaction; however, the diastereo- and regioselectivities are inversed compared to the corresponding uncatalyzed reactions.226 The presence of the Lewis acid was proposed to change the interaction between the azomethine ylide and the alkene from a dominant HOMOdipole-


LUMOalkene interaction to a LUMOdipole-HOMOalkene interaction, but no thorough investigations were performed.226 The suggested FMO interaction between the azomethine ylide and maleimide leading to the endo diastereomer is presented in 218.223

Moloney et al. have extended this reaction further by reaction of 214 (R3 ) H) with a variety of unactivated alkenes and alkenes having an EWG substituent and found that the 1,3-DC products can be successfully deprotected to give chiral, functionalized proline derivatives.233 Chiral aziridines have also been used as precursors for azomethine ylides.234-239 Photolysis of the aziriScheme 33


dine 219 produces the azomethine ylide 220, which was found to add smoothly to methyl acrylate 221a (Scheme 33).235,237-239 The 1,3-DC reaction proceeds with little or no de, but this was not really surprising as the chiral center in 220 is somewhat remote from the reacting centers of the azomethine ylide. The de can be improved significantly by substitution of the acrylate with chiral ligands; especially, the concomitant use of the acrylate of Oppolzer’s chiral sultam 221b leads to the formation of the exo adduct in reasonable yields and with >90% de. These results are in sharp contrast to the results obtained by the use of chiral acryl esters as dipolarphiles, which react with 220, giving no appreciable facial selectivity. A 1,3-DC reaction related to the one outlined in Scheme 33 has been used for the asymmetric synthesis and complete structure elucidation of (-)quinocarcin 223.235 Garner et al. later demonstrated that using aziridines substituted with Oppolzer’s sultam leads to an azomethine ylide precursor 224 which adds to various electron-deficient alkenes, such as dimethyl maleate, N-phenylmaleimide and methyl acrylate, giving the 1,3-DC product in good yield and up to 82% de for N-phenylmaleimide.234 Aziridines, such as 225, have also been used as precursors for the chiral azomethine ylide, but in reactions with vinylene carbonates relative low de were obtained.236

Azomethine ylides 227 derived from (5S,6R)-2,3,5,6tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (226) and various aldehydes have been prepared and used in the 1,3-DC with dimethyl maleate (Scheme 34).240 In the case of higher aliphatic and aromatic aldehydes the endo selectivity in the 1,3-DC reaction was excellent, but the stereoselectivity of the C-7 position of 228sthe carbon atom to which the aldehyde substituent is boundswas generally low, due to the syn-anti interconvertion of the R substituent in 227. However, as an exception the use of isobutyraldehyde gave selectively a single diastereomer in the reaction. The 1,3-DC products 228 are converted into the corresponding pyrrolidines 229, which proved to have high ee’s.240 Other chiral azomethine ylides, derived from 2-(tertbutyl)-3-imidazolidin-4-one, have also been tested as chiral controller in 1,3-DC reactions.241 2-(tert-Butyl)3-imidazolidin-4-one reacted with various aldehydes to produce azomethine ylides, which then were reacted with a series of different electron-deficient alkenes to give the 1,3-DC products in moderate diastereoselectivitysup to 60% de. Azomethine ylides 232 can be generated from tertiary amine N-oxides 230 by reaction with LDA (Scheme 35).242 Several different chiral R*-substituted azomethine ylides 232 prepared in this manner were used in the 1,3-DC reaction with alkenes, but the de’s obtained of the products 233 were low.



Scheme 34

Scheme 35

Other 1,3-DC reactions of chiral azomethine ylides with C60243 and reactions of chiral azomethine ylides derived from 1-benzyl-4-phenyl-2-imidazoline with different electron-deficient alkenes have been performed.244

5.2. Chiral Alkenes In a series of papers Grigg et al. have studied the 1,3-DC reaction of various azomethine ylides with chiral alkenes.245-253 The principle for the reaction is outlined in eq 35. The metallaazomethine ylide 234 reacts with an electron-deficient alkene, such as menthyl acrylate 91, when M ) Ag(I), Li(I), Tl(I), or Ti(IV) to give the 1,3-DC product 235 in good yield and with high endo and diastereofacial selectivity induction with de’s up to >95% (eq 35). The azomethine ylide substrates for the 1,3-DC reaction can be both aromatic, heteroaromatic and aliphatic aldimines. It is observed that the use of 234 and Ti(OiPr)3Cl as the metallaazomethine ylide gives a reversal of the regioselectivity in the 1,3-DC reaction with 91 while retaining the stereospecificity.249

The 1,3-DC reaction of azomethine ylides with menthyl acrylate is significantly slower compared with the analogous reaction of methyl acrylate as the dienophile, which often leads to lower yield due to a slow metal ion induced hydrolysis of the imine by traces of water. However, this can be overcome by the addition of a base and the stronger the base the faster the reaction.246,247 The mechanism of the 1,3DC reaction of these metallaazomethine ylides generated from imines by the action of amine bases in combination with especially LiBr and AgOAc has been studied extensively.247 It has e.g. been found by the application of X-ray analysis of a series of representative cycloadducts that the established absolute configuration of the pyrrolidine stereocenters is independent of the metal salt and the size of the pyrrolidine C-2-substituent for a series of aromatic and aliphatic imines. On the basis of the observed regioselectivities, endo selectivities, and diastereofacial selectivities of the 1,3-DC reaction and with the absolute configuration of the products, a transition state model 236 for the facial shielding effect of the menthyl isopropyl moiety was proposed (eq 36).245,247

The azomethine ylides 237, generated from both aromatic and aliphatic imines of R-amino acids, react with chiral cyclic alkenes 238, such as 5-menthyl2(5H)-furanone (R3 ) menthyl) (eq 37) in the presence silver acetate and various bases.246,254 The 1,3DC products 239 are formed with complete regioselectivity and endo selectivity with >95% de via the syn dipoles. The proper choice of base showed the to be 2-tert-butyl-1,1,3,3-tetramethylguanidine > DBU > NEt3. By the use of a chiral 5(R)-lactam in the reaction with 237 leads to optical pure cycloadducts.246 Feringa et al. used 5-methoxy-2(5H)-furanone 238 (R3 ) Me) in the reaction with an ester-substituted


azomethine ylide prepared in situ from N-benzylglycine and formaldehyde.254 In this reaction four 1,3-DC products were formed, but although the regioselectivity was poor, a complete anti-π diastereofacial selectivity was observed. Related cyclic alkenes have also been used by Wee,255 giving high diastereofacial selectivity, whereas for the acyclic alkenes the π-facial selectivity and mode of 1,3-DC reaction is dependent on the structure of the alkene. Hegedus et al. have prepared optically active 4,4disubstituted butenolides by photolysis of chromium alkoxycarbene complexes with optically active enecarbamates, followed by Baeyer-Villiger oxidation.86 These butenolides react with both achiral and chiral azomethine ylides, but low diastereoselectiveties were found. In a series of papers Kanemasa et al. have used the concept of lithium bromide/Et3N-mediated 1,3DC reactions of N-alkylidene-2-amino esters and amides with chiral electron-deficient alkenes.256-260 These reactions proceed with high regio- and stereoselectivities. The first diastereoselective 1,3-DC reaction of chiral alkenes with azomethine ylides from Kanemasa et al. was by the use of R,β-unsaturated carbonyl compounds bearing a 2-pyrrolidinyl chiral controller, or analogues.258,259 The reaction of methyl (benzylideneamino)acetate (240) with methyl (3R,7aS)-2-phenylperhydropyrrole[1,2-c]imidazole3(E)-propenoate (241) is outlined in eq 38. The reaction proceeds well in the presence of LiBr and DBU with complete regioselectivities, endo selectivities, and diastereofacial selectivities by attack of the syn-azomethine ylide to the R-si face of the alkene. If the metal is changed from lithium to magnesium a slower reaction is observed.259 The 1,3-DC product 242 can easily be converted to polyfunctionalized 2,4pyrrolidinedicarboxylates. The two epimers of methyl (E)-3-[(4S)-3-benzyl-4isopropyloxazolidin-2-yl]propenoate 243a,b (which could not be separated by chromatography) were also reacted with methyl(benzylideneamino)acetate 240 under the same reaction conditions as above. Two diastereomers, corresponding to the epimers of the chiral alkene, of the 1,3-DC product were formed, indicating a reaction with an absolute diastereofacial selectivity. The absolute stereochemistry of the minor cycloadduct was assigned by X-ray analysis.258 The work has been extended to include R,β-unsaturated esters bearing a C2-symmetric imidazolidine


chiral controller at the β position, such as 244.257 The 1,3-DC reaction of the azomethine ylide 240 with 244 leads to the formation of the cycloaddition product in high yield and with a satisfactory de of 92%. The reaction was found to be very dependent on the substituents in both 240 and 244. Reactions in which the R substituent in 240 is tert-butyl and the R substituent in 244 methyl, high stereocontrol is achieved. If the methyl substituent in 244 is exchanged with phenyl a lower selectivity is observed. The reaction proceeds under HOMOdipole-LUMOalkene control with the dipole approaching the si face of the alkene as the re face is hindered by the R substituent as outlined 245.

A related approach has been applied by Waldmann et al. who used N-acryloyl-(S)-proline esters 246 as the chiral alkenes.261,262 The 1,3-DC reaction of 246 with metallaazomethine ylides (especially Li(I)) derived from imines 247 with aliphatic and aromatic amino acids gave the desired cycloadduct 248 with almost complete endo selectivity (>99:98% (eq 39). To account for the high selectivity in this 1,3-DC reaction, it was proposed that the lithium cation is coordinated to both the azomethine ylide and to 246 in the transition state and that it coordinates through the amide and ester carbonyl groups in 246 in such a way that the acryl amide must possess a cis-anti conformation.261,262 The azomethine ylide derived from 249 has also been used in the reaction with chiral (E)-γ-alkoxy-



R,β-unsaturated esters 250 (eq 40). The corresponding tetrasubstituted pyrrolidines are obtained with complete regiocontrol in fair to excellent de.263

The 1,3-DC reaction of chiral R,β-unsaturated ketones 253, substituted by alkoxy or amino groups in the γ position, with the azomethine ylide derived from 252 have also been investigated (eq 41).264,265 The reaction proceeds in the presence of LiBr to give a diastereomeric mixture of 254, whereas using AgOAc leads to a highly regio- and diastereoselective reaction, with de’s >90%. The use of AgOAc gave a higher yield of 254 compared with the use of LiBr. The reactivity is also dependent on the substituents in the azomethine ylide, as the use of carboxamides (R2 ) NH2) leads to a slower reaction compared with the use of glycine esters (R2 ) OEt). Furthermore, the use of the AgOAc/DBU system also allowed the use of aliphatic amines (R2 ) cyclohexyl). The 1,3DC reaction of 252 and 253a-e is very dependent on the chiral substituent R* and the highest stereoselectivity was achieved using the bulky dibenzylamino substituent in the γ position (253d,e). On the basis of an X-ray analysis of the major isomer 254a an anti orientation of the substituents at C-3 and the stereocenter C-1′ of the R*-substituent was found. This anti orientation was accounted for by the inside

alkoxy effect described by Houk et al.,266,267 by which the major stereoisomer is formed by an attack of the azomethine ylide with the alkene oriented away from the most bulky alkyl moiety. The alkoxy substituent thus occupies the stereoelectronically favored inside position and the small hydrogen atom the crowded outside region (vide infra).264 Meyers et al. have studied the addition of azomethine ylides 255 to chiral unsaturated bicyclic lactams 256 (eq 42).268-271 The diastereoselectivities are dependent on the various substituents R1-R.4 For R1 ) Me, Ph, the major storeoisomer obtained is 257 (eq 42), whereas for R1 ) H the other diastereomer is formed.269 Furthermore, it was found that for R3 ) H, the π-facial selectivity is insensitive to the chiral substituents of the dipole (R4 ) chiral group), whereas for R3 ) CO2Me or CO2t-Bu lower selectivities were observed.268 On the basis of the experimentally observed results the approach of the chiral azomethine ylide to the alkene as outlined in 258 was suggested. The 1,3-DC reaction of these azomethine ylides with chiral unsaturated bicyclic lactams was used for the synthesis of the (+)-conessine precursor (+)-benzohydrindan 259.270


Cross-conjugated polyenones bearing a planar chirality introduced by an organometallic moiety have also been reacted with an azomethine ylide in a 1,3-DC reaction, but low diastereoselectivity was observed.272 The 1,3-DC reaction of (R)s-p-tolyl vinyl sulfoxide 261 with 1-methyl-3-oxidopyridinum 260 gave three of the four possible diastereomers, and one of these isomers 262 was used for the enantioselective synthesis of (1S)-(-)-2R-tropanol 263 (Scheme 36).273 Scheme 36


of acromelic acid A 268 uses aziridine 265 as precursor and the reaction, which proceeds with very high diastereofacial selectivity to give 267, is proposed to go via intermediate 266.275 A related approach was used by Weinreb et al. for the racemic construction of the tricyclic core of the marine alkaloid sarine A.278 Nearly the same approach was used by Heathcock et al. for a racemic intramolecular 1,3-DC reaction of stabilized azomethine ylides to unactivated alkenes.279 Ogasaware et al. used also this approach for the synthesis of the necine base dihydroxyheliotridane.280 Garner et al. have used an intramolecular 1,3-DC reaction of azomethine ylides with alkenes related to the intermolecular reaction outlined in Scheme 33 (vide supra).281 The syntheses of naphthyridinomycin and quinocarcin were based on the introduction of an electron-deficient alkene as the R substituent in 219 (Scheme 33) to which the azomethine ylide moiety of 220 adds diastereoselectively in a 1,3dipolar fashion. The work has been extended to a silicon-based tethered reaction and an example of the reaction of 269 is shown (eq 43).282 It was found that

(5R,6S)-2,3,5,6-Tetrahydro-5,6-diphenyl-1,4-oxazin2-one has been used as precursor for the formation of chiral alkenes 264 which was reacted with Nbenzyl-N-(methoxymethyl)trimethylsilylmethylamines in a key reaction for the asymmetric synthesis of (S)-(-)-cucurbitine.274

5.3. Intramolecular Reactions Asymmetric intramolecular 1,3-DC reactions of azomethine ylides with alkenes has mainly been utilized in relation to total synthesis and with aziridines as the precursors for the azomethine ylide. Takano et al. used this approach for the synthesis of natural products, such as acromelic acid A (268),275 (-)-kainic acid,276 and (-)-mesembrine277 where thermolysis of the aziridine was used to generate the azomethine ylide required for the intramolecular reaction as presented in Scheme 37. The synthesis Scheme 37

reactions with products with a ring size greater than nine atoms lead to preference for the 1,3-DC products such as 270 arising from a si-face attack, whereas reactions with products with a ring size equal to nine atoms lead to the opposite face selection. Both methyl and phenyl substituents, in the tether gave a similar results.282 The intermolecular approach developed by Harwood et al. shown in Scheme 32 (vide supra) has been extended to also include intramolecular reactions.227,228 The reaction of the chiral template 271 with the alkenyl aldehyde 272 leads to the formation of the azomethine ylide 273, which undergoes an intramolecular 1,3-DC reaction to furnish 274 (Scheme 38). The reaction is found to proceed with high diastereoselectivity as only one diastereomer of 274 is formed. By a reduction of 274, the proline derivative 275 was obtained. It should also be noted that the intermolecular reaction between alkenes and nonstablized azome-



Scheme 38

It has also been found that Ag(I) salts in combination with chiral ligands can catalyze similar 1,3-DC reaction with ee’s of about 70%.245

6. Other Allyl Anion Type Dipoles

thine ylides generated from tertiary amine N-oxides presented in Scheme 35 (vide supra) has been extended to an intramolecular reaction.283

5.4. Metal-Catalyzed Reactions Grigg et al. have found that chiral Co(II) and Mn(II) complexes are excellent catalysts for the 1,3-DC reaction of azomethine ylides derived from arylidene imines of glycine.284 Reaction of the azomethine ylides 276 with methyl acrylate 277 in the presence of a stoichiometric amount of Co(II) and the chiral ephedrine ligand gave the best yield and ee of the 1,3-DC product 278 (eq 44).

Contrary to the numerous reports on asymmetric 1,3-DC reactions of nitronates, azomethine ylides and especially nitrones, only a few asymmetric 1,3-DC reactions of other allyl type dipoles have been reported and they will be presented in the following.

6.1. Azomethine Imines The 1,3-DC reaction of azomethine imines 280 with alkenes 281 leads to the formation of pyrazolines 282 (eq 45).

The use of azomethine imines in asymmetric 1,3DC reactions with alkenes is limited, and the attention has been focused on the use of chiral azomethine imines for the stereoselective synthesis of C-nucleosides. The dihydropyrazole derivative 283 has been transformed into chiral azomethine imines, such as 284 by reaction with carbohydrate-derived aldehydes.285 The 1,3-DC reaction of 284, as well as other chiral azomethine imines, with methyl acrylate affords the nucleoside 285 (Scheme 39). The 1,3-DC reactions Scheme 39

The yields of 278 were in the range of 45-84% and the ee’s up to 96%, with the highest ee obtained when Ar ) 2-naphthyl, 4-BrC6H4, or 4-MeOC6H4, and when methyl acrylate was used as the solvent. Both the reaction time and ee are dependent on the counteranion, as the use of CoF2 as the catalyst leads to a very slow 1,3-DC reaction with low chiral induction compared with the use of CoCl2.284 A proposed working model for the asymmetric induction is shown in 279. The cis arrangement of the methyl and phenyl group of the ligand result in a pseudoequatorial conformation of the phenyl group and provides an effective blockade of one face of the dipole.284


were found to be highly stereoselective with >95% de in nearly all the reactions studied.285-287

6.2. Carbonyl Oxides Carbonyl oxides are very reactive intermediates in the ozonolysis of alkenes and they are known to react immediately in a 1,3-DC reaction with the aldehyde or ketone formed by decomposition of the primary ozonide.288 However, by the ozonolysis of enol ethers the primary ozonide undergoes cleavage to give carbonyl oxides and esters and the esters are unreactive toward carbonyl ylides. Thus, the carbonyl ylide can be trapped.289 Only a few reactions of this type have been reported and to our knowledge only in work by Casey and Culshaw has the diastereofacial electivity of this reaction been studied.290 By the ozonolysis of the racemic enol ether 286, rac-288a, and rac-288b were obtained in a 3:1 ratio (Scheme 40). The products are formed in a 1,3-DC reaction Scheme 40


a pair of enantiomers in which the relative configuration between the 4- and 5-substituents is determined from the geometry of the alkene. Generally, nitrile oxides react with terminal alkenes to give the 5-isomer of the isoxazoline, i.e. the nitrile oxide carbon atom attacks the terminal carbon atom of the alkene.

The 2-isoxazolines 292 formed in the reaction between nitrile oxides and alkenes are useful building blocks, since they are readily converted into 3-hydroxycarbonyl compounds 293 upon a mild reduction with retention of the configuration of the chiral centers (eq 47).291 Other useful functional groups, such as 3-amino alcohols, may also be obtained from isoxazolines.21,291

Due to the versatility of this reaction for the construction of chiral compounds, the demand for asymmetric versions of this reaction has increased over the last 20 years. Thus, several publications on asymmetric 1,3-DC reactions of nitrile oxides with alkenes have appeared. The majority of the reactions described involve optically active alkenes or are intramolecular reactions. However, during the last 5 years the application of metal catalysts in this reaction for control of the stereoselectivity has been described.

7.1. Chiral Nitrile Oxides

from the reactive intermediate 287. By hydrogenolysis of rac-288a the naturally occurring 1,3-diol rac289 was obtained in an overall yield of 41%.290

7. Nitrile Oxides The 1,3-DC reaction of nitrile oxides with alkenes provides a straightforward access to 2-isoxazolines and the reports on synthetic application of this reaction are numerous (eq 46).21,291-293 The nitrile oxide can be formed either in the Mukaiyama reaction from a primary nitro compound and phenyl isocyanate,294 or from an aldoxime by treatment with a chlorinating agent and a weak base.21,291,295 Nitrile oxides 290 are almost always generated in situ in order to avoid dimerization. The 1,3-DC reaction of a nitrile oxide 290 with an alkene 291 can give rise to two regioisomers of the 2-isoxazoline 292, each as

Only a few reports have described the application of optically active nitrile oxides in 1,3-DC reactions.267,295-297 A few reactions involving racemic nitrile oxides have also been published.298,299 In the first report Tronchet et al. report the application of a glucoside-derived nitrile oxide 294 in the reaction with styrene; however, no selectivity was observed, since the product was obtained as a 1:1 mixture of two diastereomers.297 In later work by others the glyceraldehyde-derived nitrile oxide 295 was subjected to 1,3-DC reactions with alkenes, but, very low or absence of diastereoselectivity was found.295,299


Kozikowski et al. describe the application of glyceraldehyde-derived nitro compound 296, which upon treatment with phenyl isocyanate and base is converted into nitrile oxide 297 (Scheme 41).296 In the reaction between in situ generated 297 and (Z)-2butene the isoxazoline 298 is formed in 49% de. Scheme 41

In more recent work Kim et al. demonstrated that by the concomitant application of the chiral nitrile oxide 300, in this case obtained from the oxime 299, and a chiral alkene, selectivities of up to 84% de were obtained of product 301 in the 1,3-DC reaction (Scheme 42).300 However, as shall be shown later in this chapter, even better selectivities have been obtained in reactions of achiral nitrile oxides with the acrylate of Oppolzer’s chiral sultam. Scheme 42


auxiliaries attached to acrylates, and chiral auxiliaries attached to acryl amides. Annunziata et al. performed a study on the reaction of the protected allylic alcohol rac-302 with nitrile oxides (eq 48).301 The alkenes applied were racemic; however, for most derivatives the product isoxazolines rac-303 and rac-304 were obtained with high diastereoselectivities with a preference of rac-303 of 87-96% de.

Studies toward the understanding of the stereochemical outcome of the addition of nitrile oxides to chiral allyl ethers have been performed.266,267,302 According to Houk et al. the major product arises from transition state A in which the largest group (L) occupies the anti position, the medium group (M) the inside position, and the smallest group (S) occupy the outside position (Figure 5).266,267 Out of the other five possible conformations the minor product is proposed to arise from transition state B. It is assumed that the inside position is less sterically demanding than the outside position due to the oxygen atom of the incoming nitrile oxide. This proposal is in good agreement with the experimentally obtained selectivities;266,267,301-303 however, if the medium group is a hydroxy group, transition state C (similar to B) is favored, due to hydrogen bonding of the nitrile oxide oxygen atom to the hydroxy group.302

7.2. Chiral Alkenes Contrary to the small number of publication dealing with 1,3-DC reactions of chiral nitrile oxides with alkenes several research groups have applied optically active alkenes in these reactions. The description of reactions of the various different types of chiral alkenes is divided in two major parts: (i) alkenes in which the chiral center is located vicinal to the double bond, which includes allylic alcohols, allylic amines, and chiral vinyl sulfoxides, and (ii) derivatives in which the chiral center is located two or more bonds from the alkene moiety. The latter part includes vinyl ethers, metalla complexes, chiral

Figure 5. A model for the transition state of the 1,3-DC reaction of nitrile oxides to alkenes.266,267

As a crucial step in the synthesis of 2-deoxy-Dribose Kozikowski and Ghosh reported the 1,3-DC reaction between the glyceraldehyde-derived alkene 305 and nitrile oxide 306 (eq 49).304,305 The reaction proceeds with fair selectivity, and the isoxazolidine 307 is obtained as the major isomer with 60% de. By



the application of other nitrile oxides selectivities of up to 86% de were observed in the reaction with 305.306 Reactions of nitrile oxides with alkenes similar to 305 have also been investigated by others.303,307

sulfoxides such as 315 have been applied in 1,3-DC reactions with various benzonitrile oxides (eq 51).312

Martin et al. utilized the chiral bicyclic lactone 308 in the enantioselective total synthesis (+)-phyllanthocin (311).308 The 1,3-DC reaction between 308 and 309 proceeds in refluxing toluene to give 310 in a yield of 45% along with 15% and 19% of other diastereo- and regioisomers, respectively (Scheme 43). After several further synthetic steps compound 311 was obtained from 310. Scheme 43

Feringa et al. synthesized an optically active L(menthyloxy)furanone 67 as described in section 3.2 (Scheme 8). This chiral alkene was also subjected to 1,3-DC reactions with benzonitrile oxide and the reactions proceeded with a high degree of selectivity to furnish the products in regioisomeric ratios of >90: 10, each as a single diastereomers.84,85 Chiral allylamines 312 have been applied in reactions with benzenesulfonylcarbonitrile oxide 313 by Wade et al. (eq 50).309 The reaction proceeds at 3550 °C to give product 314 in reasonable yields, but the diastereofacial selectivities were modest. Racemic allylsilanes have also been applied in the 1,3-DC reaction with nitrile oxides but moderate diastereoselectivities were obtained.310,311 The chiral allylic center may also be a sulfur or phosphorus atom. Fluoro-substituted chiral vinyl

The reaction proceeds slowly at rt; however after 5-10 days the isoxazoline 316 is obtained with an excellent de in good yield. In some cases the product tends to eliminate the 5-methoxy substituent of the isoxazoline, thus, under loss of two chiral centers, an isoxazole is obtained.312,313 Other chiral sulfinyl derivatives have also been applied in 1,3-DC reactions with nitrile oxides314,315 and in one case a racemic vinylphosphine oxide was applied in the reaction with various nitrile oxides, but with moderate selectivities.100 In all the above-described reactions, the chiral center of the alkene was located in the allylic position; however, as shall be demonstrated in the following part, more distant chiral centers may also lead to highly selective 1,3-DC reactions with nitrile oxides. The optically active alkene 317 obtained from (S)methyl cysteine, reacts with 3,5-dichlorobenzonitrile oxide at rt to furnish the spiroisoxazoline 318 as the sole regio- and diastereomer in 72% yield (eq 52).316

Nitrile oxides are relatively electron-deficient compounds and react smoothly with electron-rich vinyl ethers. Jenkins et al. investigated the reactions of L-menthyl, 8-phenylmenthyl, and (1S)-endo-bornylvinyl ethers with nitrile oxides, but generally the de’s were 98% de in the reaction with benzonitrile oxide.

For all the adducts 335, 337-341 the chiral auxiliary was recovered by reaction with L-selectride under formation of the optically active isoxazolinylmethanols 342 (eq 57). Curran’s chiral auxiliary in 337 has also been applied in reactions of β-substituted acryloyl deriva-


tives with nitrile oxides.328 The reactions offer similar high selectivities, but mixtures of regioisomers are obtained. A fumaric acid derivative in which one of the carbonyl groups were reduced and linked via an cyclic aminal to a chiral 1,2-diamine auxiliary (see eq 38) was subjected to a 1,3-DC reaction with nitrile oxides.332 Despite moderate yields and mixtures of regioisomers, the products were occasionally obtained with a high degree of diastereoselectivity.

7.3. Intramolecular Reactions The intramolecular 1,3-DC of nitrile oxides, often abbreviated INOC, with alkenes is an effective tool for the construction of bi- and polycyclic isoxazolines.17,21,116,146,292,338 Due to the rigid linear structure of the nitrile oxide the reaction of alkenylnitrile oxides almost always proceeds to give bicyclo[x,3,0] derivatives for x ) 3-5 (eq 58).

Like other intramolecular reactions it is easier to control the stereoselectivity than in the intermolecular counterpart. The chiral center(s) controlling the diastereoselectivity of the reaction can be located outside the bicyclic isoxazoline formed and this type of reactions will be described first. Most frequently the diastereoselectivity is controlled by a chiral center in the rings formed which will be presented next. The alkenyl nitrile oxides derived from sugar derivatives will finally be reviewed. According to our knowledge no reports have appeared on metal-catalyzed/assisted INOC reactions. In 1987 three papers on the application of 5- and 6-alkenylnitrile oxides were published by Annunziata et al. in which the chiral center was an allylic ether located outside the ring formed.339,340 The nitrile oxide was formed by chlorination of the oxime 343, and the reaction proceed at 0 °C to give the product 344 with a de of up to 72% (eq 59). The reactions of


both (E)- and (Z)-alkenes were tested and similar selectivities were obtained. They also applied 5-alkenylnitrile oxides in which one of the methylene groups in the ring was substituted by a sulfur atom.339 In one case a diastereoselectivity of 90% de was obtained by using the sulfur derivative. In earlier studies Kozikowski and Chen utilized a related reaction in the total synthesis of (+)-paliclavine.341,342 The reaction of racemic 5-alkenylnitrile oxides in which the chiral center is located in the resulting ring was applied by Kozikowski and Stein in the synthesis of (()-sarkomycin (347, Scheme 46).343 The nitrile oxide is generated from nitroalkene 345 and reacts to give rac-346 as the single diastereomer in 55% yield. In two additional steps (()-sarkomycin (347) was obtained. Similar reactions of racemic 5-alkenyl nitrile oxides were investigated by Kurth et al. and depending on the substituent of the generated ring low to excellent selectivities were obtained.344 Scheme 46

An optically active 3-flouro-5-alkenyloxime 348 was applied in the INOC reaction by Resnati et al. (eq 60).125 The nitrile oxide generated in situ from 348, attacks preferently the face of the alkene moiety trans to the benzyloxy substituent, to give the bicyclic product 349 with 60% de.

Fukumoto et al. applied the optically active bicyclic alkenylnitrile oxide 350 precurser in the synthesis of triquinanes (eq 61).345 The starting material for the reaction of 350 consisted of a 1:2 mixture of epimers at the chiral center connected to the methoxycarbonyl moiety; however, the reaction proceeded with complete face selectivity to give the two pure epimers of 351.



Reactions of 7-alkenylnitrile oxides have also been described. The glucose-derived oxime 358 was transformed into the corresponding nitrile oxide which reacted to give 359, and the reaction is an effective method for the construction of seven-membered rings such as 359, which was obtained in 65% yield as the sole isomer as in eq 63 but a de of only 13% was reported.132,352

7.4. Metal-Catalyzed Reactions

The same authors applied a 6-alkenylnitrile oxide in the synthesis of testosterone.346 Reactions of 6-alkenylnitrile oxide were extensively studied by Shishido et al. who applied this approach in the syntheses of (+)-albicanol,347 (-)-mintlactone,348 (+)isomintlactone,348 (+)-menthofuran,349 and (+)-cassiol 355.350 The INOC reaction performed in the synthesis of the latter compound is outlined in Scheme 47. The oxime 352 was treated with aqueous sodium hypochlorite and base to generate the nitrile oxide, which reacted to give 354 as the sole product in 88% yield. It is proposed the reaction proceeds via transition state 353a. By the use a Monte Carlo search for optimized structures of transition states of compounds very similar to 353a and 353b, it was found that transition state 353a is favored by 3.7 kcal/mol over 353b.350 As described for nitrones (vide supra) the carbohydrate skeleton provides an effective basis for the induction of stereoselectivity in intramolecular 1,3DC reactions. In a contribution from Takahashi et al. the mannitol-derived oxime 356 underwent INOC upon chlorination in the presence of a base to give 357 as the sole product (eq 62).351 The stereochemical outcome of the reaction was predicted using the same line of reasoning as described above. The product 357 was an adduct in the synthesis of a trihydroxyvitamin D3 synthon.351 Theoretical calculations provided a rationale for the 1,3-DC product as a chairlike transition state was calculated to be 3.6 kcal/mol lower in energy than the boatlike transition state.351

Compared to the related reactions of nitrones there have only appeared a few publications on metalassisted or metal-catalyzed 1,3-DC reactions of nitrile oxides. Some of the obstacles for controlling the stereoselectivity with metal complexes are (i) most nitrile oxides are very reactive short-lived species that must be generated in situ, (ii) in the two general procedures for the generation of nitrile oxides, bases such as triethylamine are used, which may destroy the catalyst, and (iii) the nitrile oxide have low-lying FMOs and therefore attempts to use the traditional activation of R,β-unsaturated carbonyl compounds with Lewis acids would probably fail. At least one of these obstacles was overcome by Kanemasa et al.353-357 Instead of using amines as bases for the generation of the nitrile oxide they applied alkylmagnesium bromide or alkoxymagnesium bromide (Scheme 48). The nitrile oxide is Scheme 48

smoothly generated at low temperature under these conditions probably coordinated to the magnesium salt. In the reaction of chiral allylic alcohols with nitrile oxides generated by the conventional method, low diastereoselectivity is mostly obtained; however, when the magnesium alkoxide is mixed with hydroximoyl chloride 360, the resulting nitrile oxide


reacts with the alkene to give 363 with a syn selectivity of up to 98% de. It is proposed that the syn selectivity and also rate accelerations observed are due to chelation via the metal salt. Of the two transition states syn-364 and anti-364, the former is favored since steric repulsion between the substituent at the chiral center and the allylic proton is to be expected.353,354,356 In reactions of 1,2-disubstituted alkenes of allylic alcohols this approach also offers an excellent control of the regioselectivity.353,355

Ukaji et al. applied a related approach to the first and so far only asymmetric metal-catalyzed 1,3-DC reaction of nitrile oxides with alkenes.204,205 Upon treatment of allyl alcohol 365 with diethylzinc and (R,R)-diisopropyl tartrate, followed by the addition of diethylzinc and substituted benzoximoyl chlorides 366, the isoxazolidines 367 are formed with impressive enantioselectivities of up to 96% ee (eq 64).204

In an extension of this work they developed a catalytic version of the reaction in which the chiral ligand (R,R)-diisopropyl tartrate (DIPT) was applied at a concentration of 20 mol %.205 Despite the reduction of the amount of the chiral ligand similar high enantioselectivities of up to 93% ee are obtained in this work. The addition of a small amount of 1,4dioxane prove to be crucial for the enantioselectivity of the reaction. A proposal for the reaction mechanism was given, and it is outlined in Scheme 49.205 Allyl alcohol 365, hydroximoyl chloride 366, and diethylzinc react to form 368, which is mixed with the ligand and an additional amount of diethylzinc to form 370. The achiral complex 368 is apparently much less activated for a 1,3-DC reaction compared 370, which controls the enantioselectivity of the reaction. The increased reactivity of 370 compared to 368 may be due to a ligand accelerating effect of DIPT when coordinated to the metal. After formation of the isoxazoline 371, the Zn-DIPT moiety of 371 proceeds in the catalytic cycle to form complex 370 with 368. When the reaction is complete 369 is hydrolyzed to give 367.205 In a rather peculiar work by Rao et al. which does not involve metal catalysis, the induction of enantio-


selectivity in 1,3-DCs of nitrile oxides with alkenes by the application of bakers’ yeast is described.358 The enantioselectivities obtained were low (90% ee have been obtained in these reactions. However, for the 1,3-DC reactions of other types of dipoles the number of contributions on asymmetric metal catalysis is very limited. In one case high enantioselectivities were obtained in a 1,3DC reactions of nitrile oxides and in another case high ee’s were obtained in a reaction of azomethine ylides. With the increased demand for optically active compounds in the future and with the development in asymmetric metal catalysis, the development of new approaches to asymmetric metal-catalyzed 1,3DC reactions is to be expected. The development of these reactions might be a difficult task to overcomes but not impossible!

13. Abbreviations

have described the reaction of the chiral iron compound 428, in which the FesNdC fragment constitutes the 1,3-dipole, with dimethyl acetylenedicarboxylate 429 (Scheme 58).388,389 After formation of the cycloadduct 430, a CO insertion occurs and 431 is obtained with a high de. In some cases compounds related to 431 were converted into pyrrolinones.388 A number of related [3 + 2] cycloaddition reactions of alkenes with C-C-C or C-C-O fragments leading to cyclopentanes or hydrofurans, respectively, have also been described.390-393 However, since such structures are not defined as 1,3-dipoles these reactions are excluded in this review.

1,3-DC Aux* BINAP BINOL Bn BNP Cbz cHex DBU DIPT EWG FMO HOMO INOC Ipc LDA LUMO MO MOM NBS p-Tol PMB rac rt TADDOL TBDMS Tf THP

1,3-dipolar cycloaddition auxiliary (chiral) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 1,1′-bi-2-naphthol benzyl 1,1′-bi-2-naphthol phosphate benzyloxycarbonyl cyclohexyl 1,8-diazabicyclo[5.4.0]undecyl-7-ene diisopropyl tartrate electron-withdrawing group frontier molecular orbitals higest occupied molecular orbital intramolecular nitrile oxide cycloaddition isopinocampheyl lithium diisopropyl amide lowest unoccupied molecular orbital molecular orbital methoxymethyl N-bromosuccinimide p-tolyl p-methoxybenzyl racemic room temperature R,R,R′,R′-tetraaryl-1,3-dioxolane-4,5dimethanol tert-butyldimethylsilyl triflouromethanesulfonyl tetrahydropyranyl

Asymmetric 1,3-Dipolar Cycloaddition Reactions TMS Tos ) Ts Tr W

trimethylsilyl p-toluenesulfonyl trityl electron-withdrawing group

14. Acknowledgments Thanks are expressed to the Danish National Science Foundation, Statens Teknisk Videnskabelige Forskningsråd, and Carlsberg Foundation for financial support. Professors M. DiMare, K. Narasaka, D. Seebach, and S. Kobayashi are thanked for sending papers prior to publication and Jo Dam Kaergaard for doing the artwork.

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